Publications by authors named "Stephen C Gammie"

53 Publications

Thyroarytenoid Muscle Gene Expression in a Rat Model of Early-Onset Parkinson's Disease.

Laryngoscope 2021 May 31. Epub 2021 May 31.

Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Wisconsin, Madison, Wisconsin, U.S.A.

Objectives/hypothesis: Voice disorders in Parkinson's disease (PD) are early-onset, manifest in the preclinical stages of the disease, and negatively impact quality of life. The complete loss of function in the PTEN-induced kinase 1 gene (Pink1) causes a genetic form of early-onset, autosomal recessive PD. Modeled after the human inherited mutation, the Pink1-/- rat demonstrates significant cranial sensorimotor dysfunction including declines in ultrasonic vocalizations. However, the underlying genetics of the vocal fold thyroarytenoid (TA) muscle that may contribute to vocal deficits has not been studied. The aim of this study was to identify differentially expressed genes in the TA muscle of 8-month-old male Pink1-/- rats compared to wildtype controls.

Study Design: Animal experiment with control.

Methods: High throughput RNA sequencing was used to examine TA muscle gene expression in adult male Pink1-/- rats and wildtype controls. Weighted Gene Co-expression Network Analysis was used to construct co-expression modules to identify biological networks, including where Pink1 was a central node. The ENRICHR tool was used to compare this gene set to existing human gene databases.

Results: We identified 134 annotated differentially expressed genes (P < .05 cutoff) and observed enrichment in the following biological pathways: Parkinson's disease (Casp7, Pink1); Parkin-Ubiquitin proteasome degradation (Psmd12, Psmd7); MAPK signaling (Casp7, Ppm1b, Ppp3r1); and inflammatory TNF-α, Nf-κB Signaling (Casp7, Psmd12, Psmd7, Cdc34, Bcl7a, Peg3).

Conclusions: Genes and pathways identified here may be useful for evaluating the specific mechanisms of peripheral dysfunction including within the laryngeal muscle and have potential to be used as experimental biomarkers for treatment development.

Level Of Evidence: N/A Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29661DOI Listing
May 2021

Creation of a gene expression portrait of depression and its application for identifying potential treatments.

Authors:
Stephen C Gammie

Sci Rep 2021 Feb 15;11(1):3829. Epub 2021 Feb 15.

Department of Integrative Biology, University of Wisconsin-Madison, Madison, USA.

Depression is a complex mental health disorder and the goal here was to identify a consistent underlying portrait of expression that ranks all genes from most to least dysregulated and indicates direction of change relative to controls. Using large-scale neural gene expression depression datasets, a combined portrait (for men and women) was created along with one for men and one for women only. The depressed brain was characterized by a "hypo" state, that included downregulation of activity-related genes, including EGR1, FOS, and ARC, and indications of a lower brain temperature and sleep-like state. MAP kinase and BDNF pathways were enriched with overlapping genes. Expression patterns suggested decreased signaling for GABA and for neuropeptides, CRH, SST, and CCK. GWAS depression genes were among depression portrait genes and common genes of interest included SPRY2 and PSEN2. The portraits were used with the drug repurposing approach of signature matching to identify treatments that could reverse depression gene expression patterns. Exercise was identified as the top treatment for depression for the combined and male portraits. Other non-traditional treatments that scored well were: curcumin, creatine, and albiflorin. Fluoxetine scored best among typical antidepressants. The creation of the portraits of depression provides new insights into the complex landscape of depression and a novel platform for evaluating and identifying potential new treatments.
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http://dx.doi.org/10.1038/s41598-021-83348-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884719PMC
February 2021

Mu opioid receptors in the medial preoptic area govern social play behavior in adolescent male rats.

Genes Brain Behav 2020 09 18;19(7):e12662. Epub 2020 May 18.

Department of Integrative Biology, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Neural systems underlying important behaviors are usually highly conserved across species. The medial preoptic area (MPOA) has been demonstrated to play a crucial role in reward associated with affiliative, nonsexual, social communication in songbirds. However, the role of MPOA in affiliative, rewarding social behaviors (eg, social play behavior) in mammals remains largely unknown. Here we applied our insights from songbirds to rats to determine whether opioids in the MPOA govern social play behavior in rats. Using an immediate early gene (ie, Egr1, early growth response 1) expression approach, we identified increased numbers of Egr1-labeled cells in the MPOA after social play in adolescent male rats. We also demonstrated that cells expressing mu opioid receptors (MORs, gene name Oprm1) in the MPOA displayed increased Egr1 expression when adolescent rats were engaged in social play using double immunofluorescence labeling of MOR and Egr1. Furthermore, using short hairpin RNA-mediated gene silencing we revealed that knockdown of Oprm1 in the MPOA reduced the number of total play bouts and the frequency of pouncing. Last, RNA sequencing differential gene expression analysis identified genes involved in neuronal signaling with altered expression after Oprm1 knockdown, and identified Egr1 as potentially a key modulator for Oprm1 in the regulation of social play behavior. Altogether, these results show that the MPOA is involved in social play behavior in adolescent male rats and support the hypothesis that the MPOA is part of a conserved neural circuit across vertebrates in which opioids act to govern affiliative, intrinsically rewarded social behaviors.
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http://dx.doi.org/10.1111/gbb.12662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643862PMC
September 2020

Complex patterns of dopamine-related gene expression in the ventral tegmental area of male zebra finches relate to dyadic interactions with long-term female partners.

Genes Brain Behav 2020 02 4;19(2):e12619. Epub 2019 Nov 4.

Department of Integrative Biology, University of Wisconsin-Madison, Madison, Wisconsin.

Dopaminergic projections from the ventral tegmental area (VTA) to multiple efferent targets are implicated in pair bonding, yet the role of the VTA in the maintenance of long-term pair bonds is not well characterized. Complex interactions between numerous neuromodulators modify activity in the VTA, suggesting that individual differences in patterns of gene expression in this region may explain individual differences in long-term social interactions in bonded pairs. To test this hypothesis we used RNA-seq to measure expression of over 8000 annotated genes in male zebra finches in established male-female pairs. Weighted gene co-expression network analysis identified a gene module that contained numerous dopamine-related genes with TH found to be the most connected gene of the module. Genes in this module related to male agonistic behaviors as well as bonding-related behaviors produced by female partners. Unsupervised learning approaches identified two groups of males that differed with respect to expression of numerous genes. Enrichment analyses showed that many dopamine-related genes and modulators differed between these groups, including dopamine receptors, synthetic and degradative enzymes, the avian dopamine transporter and several GABA- and glutamate-related genes. Many of the bonding-related behaviors closely associated with VTA gene expression in the two male groups were produced by the male's partner, rather than the male himself. Collectively, results highlight numerous candidate genes in the VTA that can be explored in future studies and raise the possibility that the molecular/genetic organization of the VTA may be strongly shaped by a social partner and/or the strength of the pair bond.
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http://dx.doi.org/10.1111/gbb.12619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582019PMC
February 2020

The circadian gene Nr1d1 in the mouse nucleus accumbens modulates sociability and anxiety-related behavior.

Eur J Neurosci 2018 Oct 16. Epub 2018 Oct 16.

Department of Integrative Biology, University of Wisconsin-Madison, Madison, WI, 53706, USA.

Nuclear receptor subfamily 1, group D, member 1 (Nr1d1) (also known as Rev-erb alpha) has been linked to circadian rhythm regulation, mood-related behavior, and disorders associated with social deficits. Recent work from our laboratory found striking decreases in Nr1d1 in the nucleus accumbens (NAc) in the maternal condition and indirect evidence that Nr1d1 was interacting with numerous addiction and reward-related genes to modulate social reward. In this study, we applied our insights from the maternal state to non-parental adult mice to determine whether decreases in Nr1d1 expression in the NAc via adeno-associated viral (AAV) vectors and short hairpin RNA (shRNA)-mediated gene knockdown were sufficient to modulate social behaviors and mood-related behaviors. Knockdown of Nr1d1 in the NAc enhanced sociability, reduced anxiety, but did not affect depressive-like traits in female mice. In male mice, Nr1d1 knockdown had no significant behavioral effects. Microarray analysis of Nr1d1 knockdown in females identified changes in circadian rhythm and histone deacetylase genes and suggested possible drugs, including histone deacetylase inhibitors, that could mimic actions of Nr1d1 knockdown. Quantitative real-time PCR (qPCR) analysis confirmed expression upregulation of genes period circadian clock 1 (Per1) and period circadian clock 2 (Per2) with Nr1d1 knockdown. Evidence for roles for opioid-related genes opioid receptor, delta 1 (Oprd1) and preproenkephalin (Penk) was also found. Together, these results suggest that Nr1d1 in the NAc modulates sociability and anxiety-related behavior in a sex-specific manner and circadian, histone deacetylase, and opioid-related genes may be involved in the expression of these behavioral phenotypes. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/ejn.14207DOI Listing
October 2018

Down-regulation of fatty acid binding protein 7 (Fabp7) is a hallmark of the postpartum brain.

J Chem Neuroanat 2018 10 1;92:92-101. Epub 2018 Aug 1.

Department of Integrative Biology, University of Wisconsin-Madison, Madison, WI, USA; Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA.

Fatty acid binding protein 7 (Fabp7) is a versatile protein that is linked to glial differentiation and proliferation, neurogenesis, and multiple mental health disorders. Recent microarray studies identified a robust decrease in Fabp7 expression in key brain regions of the postpartum rodents. Given its diverse functions, Fabp7 could play a critical role in sculpting the maternal brain and promoting the maternal phenotype. The present study aimed at investigating the expression profile of Fabp7 across the postpartum CNS. Quantitative real-time PCR (qPCR) analysis showed that Fabp7 mRNA was consistently down-regulated across the postpartum brain. Of the 9 maternal care-related regions tested, seven exhibited significant decreases in Fabp7 in postpartum (relative to virgin) females, including medial prefrontal cortex (mPFC), nucleus accumbens (NA), lateral septum (LS), bed nucleus of stria terminalis dorsal (BnSTd), paraventricular nucleus (PVN), lateral hypothalamus (LH), and basolateral and central amygdala (BLA/CeA). For both ventral tegmental area (VTA) and medial preoptic area (MPOA) levels of Fabp7 were lower in mothers, but levels of changes did not reach significance. Confocal microscopy revealed that protein expression of Fabp7 in the LS paralleled mRNA findings. Specifically, the caudal LS exhibited a significant reduction in Fabp7 immunoreactivity, while decreases in medial LS were just above significance. Double fluorescent immunolabeling confirmed the astrocytic phenotype of Fabp7-expressing cells. Collectively, this research demonstrates a broad and marked reduction in Fabp7 expression in the postpartum brain, suggesting that down-regulation of Fabp7 may serve as a hallmark of the postpartum brain and contribute to the maternal phenotype.
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http://dx.doi.org/10.1016/j.jchemneu.2018.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103884PMC
October 2018

The circadian gene Nr1d1 in the mouse nucleus accumbens modulates sociability and anxiety-related behaviour.

Eur J Neurosci 2018 08 7;48(3):1924-1943. Epub 2018 Aug 7.

Department of Integrative Biology, University of Wisconsin-Madison, Madison, Wisconsin.

Nuclear receptor subfamily 1, group D, member 1 (Nr1d1) (also known as Rev-erb alpha) has been linked to circadian rhythm regulation, mood-related behaviour and disorders associated with social deficits. Recent work from our laboratory found striking decreases in Nr1d1 in the nucleus accumbens (NAc) in the maternal condition and indirect evidence that Nr1d1 was interacting with numerous addiction and reward-related genes to modulate social reward. In this study, we applied our insights from the maternal state to nonparental adult mice to determine whether decreases in Nr1d1 expression in the NAc via adeno-associated viral (AAV) vectors and short hairpin RNA (shRNA)-mediated gene knockdown were sufficient to modulate social behaviours and mood-related behaviours. Knockdown of Nr1d1 in the NAc enhanced sociability and reduced anxiety, but did not affect depressive-like traits in female mice. In male mice, Nr1d1 knockdown had no significant behavioural effects. Microarray analysis of Nr1d1 knockdown in females identified changes in circadian rhythm and histone deacetylase genes and suggested possible drugs, including histone deacetylase inhibitors, that could mimic actions of Nr1d1 knockdown. Quantitative real-time PCR (qPCR) analysis confirmed expression upregulation of gene period circadian clock 1 (Per1) and period circadian clock 2 (Per2) with Nr1d1 knockdown. The evidence for roles for opioid-related genes opioid receptor, delta 1 (Oprd1) and preproenkephalin (Penk) was also found. Together, these results suggest that Nr1d1 in the NAc modulates sociability and anxiety-related behaviour in a sex-specific manner, and circadian, histone deacetylase and opioid-related genes may be involved in the expression of these behavioural phenotypes.
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http://dx.doi.org/10.1111/ejn.14066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113111PMC
August 2018

Genomic variants in an inbred mouse model predict mania-like behaviors.

PLoS One 2018 16;13(5):e0197624. Epub 2018 May 16.

Department of Integrative Biology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

Contemporary rodent models for bipolar disorders split the bipolar spectrum into complimentary behavioral endophenotypes representing mania and depression. Widely accepted mania models typically utilize single gene transgenics or pharmacological manipulations, but inbred rodent strains show great potential as mania models. Their acceptance is often limited by the lack of genotypic data needed to establish construct validity. In this study, we used a unique strategy to inexpensively explore and confirm population allele differences in naturally occurring candidate variants in a manic rodent strain, the Madison (MSN) mouse strain. Variants were identified using whole exome resequencing on a small population of animals. Interesting candidate variants were confirmed in a larger population with genotyping. We enriched these results with observations of locomotor behavior from a previous study. Resequencing identified 447 structural variants that are mostly fixed in the MSN strain relative to control strains. After filtering and annotation, we found 11 non-synonymous MSN variants that we believe alter protein function. The allele frequencies for 6 of these variants were consistent with explanatory variants for the Madison strain's phenotype. The variants are in the Npas2, Cp, Polr3c, Smarca4, Trpv1, and Slc5a7 genes, and many of these genes' products are in pathways implicated in human bipolar disorders. Variants in Smarca4 and Polr3c together explained over 40% of the variance in locomotor behavior in the Hsd:ICR founder strain. These results enhance the MSN strain's construct validity and implicate altered nucleosome structure and transcriptional regulation as a chief molecular system underpinning behavior.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197624PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955540PMC
December 2018

Genetic and neuroendocrine regulation of the postpartum brain.

Front Neuroendocrinol 2016 07 13;42:1-17. Epub 2016 May 13.

Department of Zoology, University of Wisconsin-Madison, Madison, WI, USA.

Changes in expression of hundreds of genes occur during the production and function of the maternal brain that support a wide range of processes. In this review, we synthesize findings from four microarray studies of different maternal brain regions and identify a core group of 700 maternal genes that show significant expression changes across multiple regions. With those maternal genes, we provide new insights into reward-related pathways (maternal bonding), postpartum depression, social behaviors, mental health disorders, and nervous system plasticity/developmental events. We also integrate the new genes into well-studied maternal signaling pathways, including those for prolactin, oxytocin/vasopressin, endogenous opioids, and steroid receptors (estradiol, progesterone, cortisol). A newer transcriptional regulation model for the maternal brain is provided that incorporates recent work on maternal microRNAs. We also compare the top 700 genes with other maternal gene expression studies. Together, we highlight new genes and new directions for studies on the postpartum brain.
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http://dx.doi.org/10.1016/j.yfrne.2016.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030130PMC
July 2016

Metabotropic glutamate receptor 3 is downregulated and its expression is shifted from neurons to astrocytes in the mouse lateral septum during the postpartum period.

J Histochem Cytochem 2015 06 4;63(6):417-26. Epub 2015 Mar 4.

Department of Zoology, University of Wisconsin-Madison, Madison, Wisconsin (CZ, SCG)

The inhibitory metabotropic glutamate receptor 3 (mGluR3) plays diverse and complex roles in brain function, including synaptic plasticity and neurotransmission. We recently found that mGluR3 is downregulated in the lateral septum (LS) of postpartum females using microarray and qPCR analysis. In this study, we used double fluorescence immunohistochemical approaches to characterize mGluR3 changes in LS of the postpartum brain. The number of mGluR3-immunoractive cells was significantly reduced in the dorsal (LSD) and intermediate (LSI) but not ventral (LSV) parts of the LS in postpartum versus virgin females. mGluR3 immunoreactivity in the LS was found predominantly in neurons (~70%), with a smaller portion (~20%-30%) in astrocytes. Colocalization analysis revealed a reduced mGluR3 expression in neurons but an increased astrocytic localization in postpartum LSI. This change in the pattern of expression suggests that mGluR3 expression is shifted from neurons to astrocytes in postpartum LS, and the decrease in mGluR3 is neuron-specific. Because mGluR3 is inhibitory and negatively regulates glutamate and GABA release, decreases in neuronal expression would increase glutamate and GABA signaling. Given our recent finding that ~90% of LS neurons are GABAergic, the present data suggest that decreases in mGluR3 are a mechanism for elevated GABA in LS in the postpartum state.
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http://dx.doi.org/10.1369/0022155415578283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872196PMC
June 2015

Glutamate, GABA, and glutamine are synchronously upregulated in the mouse lateral septum during the postpartum period.

Brain Res 2014 Dec 23;1591:53-62. Epub 2014 Oct 23.

Department of Zoology, University of Wisconsin-Madison, Madison, WI 53706, USA; Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA.

Dramatic structural and functional remodeling occurs in the postpartum brain for the establishment of maternal care, which is essential for the growth and development of young offspring. Glutamate and GABA signaling are critically important in modulating multiple behavioral performances. Large scale signaling changes occur in the postpartum brain, but it is still not clear to what extent the neurotransmitters glutamate and GABA change and whether the ratio of glutamate/GABA remains balanced. In this study, we examined the glutamate/GABA-glutamine cycle in the lateral septum (LS) of postpartum female mice. In postpartum females (relative to virgins), tissue levels of glutamate and GABA were elevated in LS and increased mRNA was found for the respective enzymes producing glutamate and GABA, glutaminase (Gls) and glutamate decarboxylase 1 and 2 (Gad1 and Gad2). The common precursor, glutamine, was elevated as was the enzyme that produces it, glutamate-ammonia ligase (Glul). Additionally, glutamate, GABA, and glutamine were positively correlated and the glutamate/GABA ratio was almost identical in the postpartum and virgin females. Collectively, these findings indicate that glutamate and GABA signaling are increased and that the ratio of glutamate/GABA is well balanced in the maternal LS. The postpartum brain may provide a useful model system for understanding how glutamate and GABA are linked despite large signaling changes. Given that some mental health disorders, including depression and schizophrenia display dysregulated glutamate/GABA ratio, and there is increased vulnerability to mental disorders in mothers, it is possible that these postpartum disorders emerge when glutamate and GABA changes are not properly coordinated.
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http://dx.doi.org/10.1016/j.brainres.2014.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312212PMC
December 2014

Addiction and reward-related genes show altered expression in the postpartum nucleus accumbens.

Front Behav Neurosci 2014 5;8:388. Epub 2014 Nov 5.

Department of Zoology, University of Wisconsin-Madison Madison, WI, USA ; Neuroscience Training Program, University of Wisconsin-Madison Madison, WI, USA.

Motherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated that postpartum (relative to virgin) NAC gene expression profile was significantly enriched for genes related to addiction and reward in five of five independently curated databases (e.g., Malacards, Phenopedia). Over 100 addiction/reward related genes were identified and these included: Per1, Per2, Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis (WGCNA) identified possible networks for transcription factors, including Nr1d1, Per2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder (BPD), and schizophrenia. Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions.
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http://dx.doi.org/10.3389/fnbeh.2014.00388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220701PMC
November 2014

Medial prefrontal cortex: genes linked to bipolar disorder and schizophrenia have altered expression in the highly social maternal phenotype.

Front Behav Neurosci 2014 2;8:110. Epub 2014 Apr 2.

Department of Zoology, University of Wisconsin-Madison Madison, WI, USA ; Neuroscience Training Program, University of Wisconsin-Madison Madison, WI, USA.

The transition to motherhood involves CNS changes that modify sociability and affective state. However, these changes also put females at risk for post-partum depression and psychosis, which impairs parenting abilities and adversely affects children. Thus, changes in expression and interactions in a core subset of genes may be critical for emergence of a healthy maternal phenotype, but inappropriate changes of the same genes could put women at risk for post-partum disorders. This study evaluated microarray gene expression changes in medial prefrontal cortex (mPFC), a region implicated in both maternal behavior and psychiatric disorders. Post-partum mice were compared to virgin controls housed with females and isolated for identical durations. Using the Modular Single-set Enrichment Test (MSET), we found that the genetic landscape of maternal mPFC bears statistical similarity to gene databases associated with schizophrenia (5 of 5 sets) and bipolar disorder (BPD, 3 of 3 sets). In contrast to previous studies of maternal lateral septum (LS) and medial preoptic area (MPOA), enrichment of autism and depression-linked genes was not significant (2 of 9 sets, 0 of 4 sets). Among genes linked to multiple disorders were fatty acid binding protein 7 (Fabp7), glutamate metabotropic receptor 3 (Grm3), platelet derived growth factor, beta polypeptide (Pdgfrb), and nuclear receptor subfamily 1, group D, member 1 (Nr1d1). RT-qPCR confirmed these gene changes as well as FMS-like tyrosine kinase 1 (Flt1) and proenkephalin (Penk). Systems-level methods revealed involvement of developmental gene networks in establishing the maternal phenotype and indirectly suggested a role for numerous microRNAs and transcription factors in mediating expression changes. Together, this study suggests that a subset of genes involved in shaping the healthy maternal brain may also be dysregulated in mental health disorders and put females at risk for post-partum psychosis with aspects of schizophrenia and BPD.
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http://dx.doi.org/10.3389/fnbeh.2014.00110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3980118PMC
April 2014

Genes showing altered expression in the medial preoptic area in the highly social maternal phenotype are related to autism and other disorders with social deficits.

BMC Neurosci 2014 Jan 14;15:11. Epub 2014 Jan 14.

Department of Zoology, University of Wisconsin-Madison, Madison, WI, USA.

Background: The mother-child relationship is the most fundamental social bond in mammals, and previous studies indicate that the medial preoptic area (MPOA) contributes to this increase in sociability. It is possible that the same genes that lead to elevated sociability in one condition (the maternal state) might also be dysregulated in some disorders with social deficits (e.g. autism). In this study, we examined whether there was enrichment (greater than chance overlap) for social deficit disorder related genes in MPOA microarray results between virgin and postpartum female mice. We utilized microarrays to assess large scale gene expression changes in the MPOA of virgin and postpartum mice. The Modular Single Set Enrichment Test (MSET) was used to determine if mental health disorder related genes were enriched in significant microarray results. Additional resources, such as ToppCluster, NIH DAVID, and weighted co-expression network analysis (WGCNA) were used to analyze enrichment for specific gene clusters or indirect relationships between significant genes of interest. Finally, a subset of microarray results was validated using quantitative PCR.

Results: Significant postpartum MPOA microarray results were enriched for multiple disorders that include social deficits, including autism, bipolar disorder, depression, and schizophrenia. Together, 98 autism-related genes were identified from the significant microarray results. Further, ToppCluser and NIH DAVID identified a large number of postpartum genes related to ion channel activity and CNS development, and also suggested a role for microRNAs in regulating maternal gene expression. WGCNA identified a module of genes associated with the postpartum phenotype, and identified indirect links between transcription factors and other genes of interest.

Conclusion: The transition to the maternal state involves great CNS plasticity and increased sociability. We identified multiple novel genes that overlap between the postpartum MPOA (high sociability) and mental health disorders with low sociability. Thus, the activity or interactions of the same genes may be altering social behaviors in different directions in different conditions. Maternity also involves elevated risks for disorders, including depression, psychosis, and BPD, so identification of maternal genes common to these disorders may provide insights into the elevated vulnerability of the maternal brain.
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http://dx.doi.org/10.1186/1471-2202-15-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906749PMC
January 2014

Endogenous CNS expression of neurotensin and neurotensin receptors is altered during the postpartum period in outbred mice.

PLoS One 2014 8;9(1):e83098. Epub 2014 Jan 8.

Department of Zoology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America ; Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

Neurotensin (NT) is a neuropeptide identical in mice and humans that is produced and released in many CNS regions associated with maternal behavior. NT has been linked to aspects of maternal care and previous studies have indirectly suggested that endogenous NT signaling is altered in the postpartum period. In the present study, we directly examine whether NT and its receptors exhibit altered gene expression in maternal relative to virgin outbred mice using real time quantitative PCR (qPCR) across multiple brain regions. We also examine NT protein levels using anti-NT antibodies and immunohistochemistry in specific brain regions. In the medial preoptic area (MPOA), which is critical for maternal behaviors, mRNA of NT and NT receptor 3 (Sort1) were significantly up-regulated in postpartum mice compared to virgins. NT mRNA was also elevated in postpartum females in the bed nucleus of the stria terminalis dorsal. However, in the lateral septum, NT mRNA was down-regulated in postpartum females. In the paraventricular nucleus of the hypothalamus (PVN), Ntsr1 expression was down-regulated in postpartum females. Neurotensin receptor 2 (Ntsr2) expression was not altered in any brain region tested. In terms of protein expression, NT immunohistochemistry results indicated that NT labeling was elevated in the postpartum brain in the MPOA, lateral hypothalamus, and two subregions of PVN. Together, these findings indicate that endogenous changes occur in NT and its receptors across multiple brain regions, and these likely support the emergence of some maternal behaviors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083098PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885409PMC
September 2014

Development of a versatile enrichment analysis tool reveals associations between the maternal brain and mental health disorders, including autism.

BMC Neurosci 2013 Nov 19;14:147. Epub 2013 Nov 19.

Department of Zoology, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Background: A recent study of lateral septum (LS) suggested a large number of autism-related genes with altered expression in the postpartum state. However, formally testing the findings for enrichment of autism-associated genes proved to be problematic with existing software. Many gene-disease association databases have been curated which are not currently incorporated in popular, full-featured enrichment tools, and the use of custom gene lists in these programs can be difficult to perform and interpret. As a simple alternative, we have developed the Modular Single-set Enrichment Test (MSET), a minimal tool that enables one to easily evaluate expression data for enrichment of any conceivable gene list of interest.

Results: The MSET approach was validated by testing several publicly available expression data sets for expected enrichment in areas of autism, attention deficit hyperactivity disorder (ADHD), and arthritis. Using nine independent, unique autism gene lists extracted from association databases and two recent publications, a striking consensus of enrichment was detected within gene expression changes in LS of postpartum mice. A network of 160 autism-related genes was identified, representing developmental processes such as synaptic plasticity, neuronal morphogenesis, and differentiation. Additionally, maternal LS displayed enrichment for genes associated with bipolar disorder, schizophrenia, ADHD, and depression.

Conclusions: The transition to motherhood includes the most fundamental social bonding event in mammals and features naturally occurring changes in sociability. Some individuals with autism, schizophrenia, or other mental health disorders exhibit impaired social traits. Genes involved in these deficits may also contribute to elevated sociability in the maternal brain. To date, this is the first study to show a significant, quantitative link between the maternal brain and mental health disorders using large scale gene expression data. Thus, the postpartum brain may provide a novel and promising platform for understanding the complex genetics of improved sociability that may have direct relevance for multiple psychiatric illnesses. This study also provides an important new tool that fills a critical analysis gap and makes evaluation of enrichment using any database of interest possible with an emphasis on ease of use and methodological transparency.
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http://dx.doi.org/10.1186/1471-2202-14-147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840590PMC
November 2013

Characterization of GABAergic neurons in the mouse lateral septum: a double fluorescence in situ hybridization and immunohistochemical study using tyramide signal amplification.

PLoS One 2013 13;8(8):e73750. Epub 2013 Aug 13.

Department of Zoology, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Gamma-aminobutyric acid (GABA) neurotransmission in the lateral septum (LS) is implicated in modulating various behavioral processes, including emotional reactivity and maternal behavior. However, identifying the phenotype of GABAergic neurons in the CNS has been hampered by the longstanding inability to reliably detect somal immunoreactivity for GABA or glutamic acid decarboxylase (GAD), the enzyme that produces GABA. In this study, we designed unique probes for both GAD65 (GAD2) and GAD67 (GAD1), and used fluorescence in Situ hybridization (FISH) with tyramide signal amplification (TSA) to achieve unequivocal detection of cell bodies of GABAergic neurons by GAD mRNAs. We quantitatively characterized the expression and chemical phenotype of GABAergic neurons across each subdivision of LS and in cingulate cortex (Cg) and medial preoptic area (MPOA) in female mice. Across LS, almost all GAD65 mRNA-expressing neurons were found to contain GAD67 mRNA (approximately 95-98%), while a small proportion of GAD67 mRNA-containing neurons did not express GAD65 mRNA (5-14%). Using the neuronal marker NeuN, almost every neuron in LS (> 90%) was also found to be GABA-positive. Interneuron markers using calcium-binding proteins showed that LS GABAergic neurons displayed immunoreactivity for calbindin (CB) or calretinin (CR), but not parvalbumin (PV); almost all CB- or CR-immunoreactive neurons (98-100%) were GABAergic. The proportion of GABAergic neurons immunoreactive for CB or CR varied depending on the subdivisions examined, with the highest percentage of colocalization in the caudal intermediate LS (LSI) (approximately 58% for CB and 35% for CR). These findings suggest that the vast majority of GABAergic neurons within the LS have the potential for synthesizing GABA via the dual enzyme systems GAD65 and GAD67, and each subtype of GABAergic neurons identified by distinct calcium-binding proteins may exert unique roles in the physiological function and neuronal circuitry of the LS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073750PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742568PMC
May 2014

Sexually dimorphic, developmental, and chronobiological behavioral profiles of a mouse mania model.

PLoS One 2013 13;8(8):e72125. Epub 2013 Aug 13.

Department of Zoology, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Bipolar disorders are heritable psychiatric conditions often abstracted by separate animal models for mania and depression. The principal mania models involve transgenic manipulations or treatment with stimulants. An additional approach involves analysis of naturally occurring mania models including an inbred strain our lab has recently characterized, the Madison (MSN) mouse strain. These mice show a suite of behavioral and neural genetic alterations analogous to manic aspects of bipolar disorders. In the current study, we extended the MSN strain's behavioral phenotype in new directions by examining in-cage locomotor activity. We found that MSN activity presentation is sexually dimorphic, with MSN females showing higher in-cage activity than MSN males. When investigating development, we found that MSN mice display stable locomotor hyperactivity already observable when first assayed at 28 days postnatal. Using continuous monitoring and analysis for 1 month, we did not find evidence of spontaneous bipolarism in MSN mice. However, we did find that the MSN strain displayed an altered diurnal activity profile, getting up earlier and going to sleep earlier than control mice. Long photoperiods were associated with increased in-cage activity in MSN, but not in the control strain. The results of these experiments reinforce the face validity of the MSN strain as a complex mania model, adding sexual dimorphism, an altered diurnal activity profile, and seasonality to the suite of interesting dispositional phenomena related to mania seen in MSN mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072125PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742520PMC
May 2014

Large scale expression changes of genes related to neuronal signaling and developmental processes found in lateral septum of postpartum outbred mice.

PLoS One 2013 22;8(5):e63824. Epub 2013 May 22.

Department of Zoology, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Coordinated gene expression changes across the CNS are required to produce the mammalian maternal phenotype. Lateral septum (LS) is a brain region critically involved with aspects of maternal care, and we recently examined gene expression of whole septum (LS and medial septum) in selectively bred maternal mice. Here, we expand on the prior study by 1) conducting microarray analysis solely on LS in virgin and postpartum mice, 2) using outbred mice, and 3) evaluating the role of sensory input on gene expression changes. Large scale changes in genes related to neuronal signaling were identified, including four GABAA receptor subunits. Subunits α4 and δ were downregulated in maternal LS, likely reflecting a reduction in the extrasynaptic, neurosteroid-sensitive α4/δ containing receptor subtype. Conversely, subunits ε and θ were increased in maternal LS. Fifteen K+ channel related genes showed altered expression, as did dopamine receptors Drd1a and Drd2 (both downregulated), hypocretin receptor 1 (Hcrtr1), kappa opioid receptor 1 (Oprk1), and transient receptor potential channel 4 (Trpc4). Expression of a large number of genes linked to developmental processes or cell differentiation were also altered in postpartum LS, including chemokine (C-X-C) motif ligand 12 (Cxcl12), fatty acid binding protein 7 (Fabp7), plasma membrane proteolipid (Pllp), and suppressor of cytokine signaling 2 (Socs2). Additional genes that are linked to anxiety, such as glutathione reductase (Gsr), exhibited altered expression. Pathway analysis also identified changes in genes related to cyclic nucleotide metabolism, chromatin structure, and the Ras gene family. The sensory presence of pups was found to contribute to the altered expression of a subset of genes across all categories. This study suggests that both large changes in neuronal signaling and the possible terminal differentiation of neuronal and/or glial cells play important roles in producing the maternal state.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063824PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661729PMC
April 2014

Mother-infant communication: carrying understanding to a new level.

Authors:
Stephen C Gammie

Curr Biol 2013 May;23(9):R341-3

Department of Zoology, University of Wisconsin, Madison, Wisconsin 53706, USA.

A recent study has found that carrying - not just holding - by human mothers has a specific calming effect on crying infants, inducing a coordinated physiological response that includes a reduction in heart rate. A similar response in mice has opened the door to elucidating the underlying neural mechanisms.
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http://dx.doi.org/10.1016/j.cub.2013.03.051DOI Listing
May 2013

Glutamic acid decarboxylase 65 and 67 expression in the lateral septum is up-regulated in association with the postpartum period in mice.

Brain Res 2012 Aug 28;1470:35-44. Epub 2012 Jun 28.

Department of Zoology, University of Wisconsin-Madison, 1117 West Johnson Street, Madison, WI 53706, USA.

The postpartum period in mammals undergoes a variety of physiological adaptations, including metabolic, behavioral and neuroendocrine alterations. GABA signaling has been strongly linked to various emotional states, stress responses and offspring protection. However, whether GABA signaling may change in the lateral septum (LS), a core brain region for regulating behavioral, emotional and stress responses in postpartum mice has not previously been examined. In this study, we tested whether the expression of two isoforms of glutamic acid decarboxylase (GAD), GAD65 (GAD2) and GAD67 (GAD1), the rate-limiting enzyme for GABA synthesis, exhibits altered expression in postpartum mice relative to nonmaternal, virgin mice. Using microdissected septal tissue from virgin and age-matched postpartum females, quantitative real-time PCR and Western blotting were carried out to assess GAD mRNA and protein expression, respectively. We found both protein and mRNA expression of GAD67 in the whole septum was up-regulated in postpartum mice. By contrast, no significant difference in the whole septum was observed in GAD65 expression. We then conducted a finer level of analysis using smaller microdissections and found GAD67 to be significantly increased in rostral LS, but not in caudal LS or medial septum (MS). Further, GAD65 mRNA expression in rostral LS, but not in caudal LS or MS was also significantly elevated in postpartum mice. These findings suggest that an increased GABA production in rostral LS of the postpartum mice via elevated GAD65 and GAD67 expression may contribute to multiple alterations in behavioral and emotional states, and responses to stress that occur during the postpartum period. Given that rostral LS contains GABA neurons that are projection neurons or local interneurons, it still needs to be determined whether the function of elevated GABA is for local or distant action or both.
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http://dx.doi.org/10.1016/j.brainres.2012.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724346PMC
August 2012

Gene expression changes in the septum: possible implications for microRNAs in sculpting the maternal brain.

PLoS One 2012 6;7(6):e38602. Epub 2012 Jun 6.

Department of Zoology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

The transition from the non-maternal to the maternal state is characterized by a variety of CNS alterations that support the care of offspring. The septum (including lateral and medial portions) is a brain region previously linked to various emotional and motivational processes, including maternal care. In this study, we used microarrays (PLIER algorithm) to examine gene expression changes in the septum of postpartum mice and employed gene set enrichment analysis (GSEA) to identify possible regulators of altered gene expression. Genes of interest identified as differentially regulated with microarray analysis were validated with quantitative real-time PCR. We found that fatty acid binding protein 7 (Fabp7) and galanin (Gal) were downregulated, whereas insulin-like growth factor binding protein 3 (Igfbp3) was upregulated in postpartum mice compared to virgin females. These genes were previously found to be differentially regulated in other brain regions during lactation. We also identified altered expression of novel genes not previously linked to maternal behavior, but that could play a role in postpartum processes, including glutamate-ammonia ligase (Glul) and somatostatin receptor 1 (Sstr1) (both upregulated in postpartum). Genes implicated in metabolism, cell differentiation, or proliferation also exhibited altered expression. Unexpectedly, enrichment analysis revealed a high number of microRNAs, transcription factors, or conserved binding sites (177 with corrected P-value <0.05) that were significantly linked to maternal upregulated genes, while none were linked to downregulated genes. MicroRNAs have been linked to placenta and mammary gland development, but this is the first indication they may also play a key role in sculpting the maternal brain. Together, this study provides new insights into genes (along with possible mechanisms for their regulation) that are involved in septum-mediated adaptations during the postpartum period.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038602PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368935PMC
November 2012

A new mouse model for mania shares genetic correlates with human bipolar disorder.

PLoS One 2012 4;7(6):e38128. Epub 2012 Jun 4.

Department of Zoology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

Bipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments attenuate this phenotype. In this study, we replicated our locomotor activity experiment, showing that MSN mice display generationally-stable mania relative to their outbred ancestral strain, hsd:ICR (ICR). We then performed a gene expression microarray experiment to compare hippocampus of MSN and ICR mice. We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7. RT-qPCR confirmed dysregulation for all of seven transcripts tested. Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21-22, 12q24, 16q24, and 17q25. Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD. Our findings suggest that MSN mice represent a polygenic model for the manic pole of BPD showing much of the genetic systems complexity of the corresponding human disorder. Further, the high degree of convergence between our findings and the human literature on BPD brings up novel questions about evolution by analogy in mammalian genomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038128PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366954PMC
October 2012

Neurotensin induced Egr-1 activity is altered in the postpartum period in mice.

Brain Res 2012 Jan 11;1433:47-55. Epub 2011 Nov 11.

Department of Zoology, University of Wisconsin, Madison, WI, USA.

Neurotensin (NT) is a 13 amino acid neuropeptide that is identical in mice and humans and is released from and acts upon a number of social brain regions. Recent work indicates NT neurotransmission may be altered in postpartum females and support the onset of some maternal behaviors. In a recent study, we highlighted how virgin and postpartum brains from mice selected for high offspring protection differ in response to injected NT (0.1 μg) relative to vehicle when examining c-Fos profiles across the CNS. In this companion study we use a second marker for brain activity, Egr-1, and evaluate multiple brain regions. Common significant increased Egr-1 responses to NT (relative to vehicle) were found in both female groups only in ventromedial hypothalamus. In lateral periaqueductal gray, virgin mice showed a significant Egr-1 increase with NT (relative to vehicle), but maternal mice did not. When comparing NT injections, virgin (relative to maternal) mice had significantly higher activity in five regions, including anterior hypothalamus, lateral hypothalamus, somatosensory cortex, paraventricular nucleus, and zona incerta; no regions were higher in maternal mice. A Principal Components Analysis was also used for data mining and in virgin mice, greater changes in activity hubs were found with NT (relative to vehicle) than for maternal mice. Overall, a lower sensitivity to NT in terms of Egr-1 reactivity in the maternal state was highlighted and this is consistent with previous c-Fos results. These findings provide additional insight into the mechanisms by which NT functions in the CNS.
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http://dx.doi.org/10.1016/j.brainres.2011.11.017DOI Listing
January 2012

Changes in CNS response to neurotensin accompany the postpartum period in mice.

Horm Behav 2011 Jul 30;60(2):177-84. Epub 2011 Apr 30.

Psychiatry Department, University of Illinois at Chicago, IL, USA.

Neurotensin (NT) is a highly conserved neuropeptide in mammals. Recent studies suggest that altered NT neurotransmission in postpartum females could promote the emergence of some maternal behaviors, including offspring protection. Here we evaluated how virgin and postpartum brains from mice selected for high maternal defense differ in response to NT. Virgin and postpartum mice were injected with either vehicle or 0.1 μg NT icv and brains were evaluated for c-Fos immunoreactivity, an indirect marker of neuronal activity. Using ANOVA analysis, common significant responses to NT were found in both female groups in four brain regions, including supraoptic nucleus, ventromedial nucleus, bed nucleus of stria terminalis dorsal, and a subregion of lateral septum (LS). For postpartum mice, only one additional region showed a significant response to NT relative to vehicle, whereas for virgin mice seven unique brain regions showed a significant c-Fos response: nucleus accumbens shell, paraventricular nucleus, central amygdala, and substantia nigra. Using a principal components analysis of c-Fos, we identified regions within each group with highly correlated activity. As expected, virgin and postpartum mice (vehicle conditions) showed different activity hubs and in the postpartum group the hubs matched regions linked to maternal care. The response to injected NT was different in the maternal and virgin groups with maternal mice showing a stronger coordinated activity in periaqueductal gray whereas virgin mice showed a stronger septal and amygdala linking of activity. Together, these results indicate neuronal responses of virgin and postpartum mice to NT and highlight pathways by which NT can alter maternal responses.
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http://dx.doi.org/10.1016/j.yhbeh.2011.04.007DOI Listing
July 2011

Maternal defense is modulated by beta adrenergic receptors in lateral septum in mice.

Behav Neurosci 2011 Jun;125(3):434-45

Department of Psychology, Northern Illinois University, USA.

Maternal defense (offspring protection) is a critical and highly conserved component of maternal care in mammalian systems that involves dramatic shifts in a female's behavioral response to social cues. Numerous changes occur in neuronal signaling and connectivity in the postpartum female, including decreases in norepinephrine (NE) signaling in subregions of the CNS. In this study using a strain of mice selected for maternal defense, we examined whether possible changes in NE signaling in the lateral septum (LS) could facilitate expression of maternal aggression. In separate studies that utilized a repeated measures design, mice were tested for maternal defense following intra-LS injections of either the β-adrenergic receptor agonist isoproterenol (10 μg or 30 μg) or vehicle (Experiment 1), the β-adrenergic receptor antagonist propranolol (2 μg) or vehicle (Experiment 2), or the β1-receptor antagonist, atenolol (Experiment 3). Mice were also evaluated for light-dark performance and pup retrieval. Thirty micrograms of the agonist isoproterenol significantly decreased number of attacks and time aggressive relative to vehicle without affecting pup retrieval or light-dark box performance. In contrast, the antagonist propranolol significantly increased maternal aggression (lowered latency to attack and increased total attack time) without altering light-dark box test. The β1-specific antagonist, atenolol, significantly decreased latency to attack (1 μg vs. vehicle) without altering other measures. Although the findings were identified in a unique strain of mice, the results of these studies support the hypothesis that changes in NE signaling in LS during the postpartum period contribute to the expression of offspring protection.
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http://dx.doi.org/10.1037/a0023184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109183PMC
June 2011

Behavioral and pharmacological assessment of a potential new mouse model for mania.

Physiol Behav 2011 Jun 22;103(3-4):376-83. Epub 2011 Mar 22.

Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States.

Bipolar disorder (BPD) is a devastating long-term disease for which a significant symptom is mania. Rodent models for mania include psychostimulant-induced hyperactivity and single gene alterations, such as in the Clock or DAT genes, but there is still a pressing need for additional models. Recently, our lab isolated a line of mice, termed Madison (MSN), that exhibit behavioral characteristics that may be analogous to symptoms of mania. In this study we quantified possible traits for mania and tested the response to common anti-BPD drugs in altering the behavioral profiles observed in this strain. Relative to other mouse lines, MSN mice showed significant elevations of in-cage hyperactivity levels, significant decreases in daytime sleep, and significant increases in time swimming in the forced swim test. In terms of sexual behavior, the MSN mice showed significantly higher number of mounts and a trend toward higher time mounting. In separate studies, olanzapine and lithium (or respective controls) were administered to MSN mice for at least 2weeks and response to treatments was evaluated. Olanzapine (1mg/kg/day) significantly decreased in-cage hyperactivity and significantly increased time sleeping. Lithium (0.2-0.4% in food) significantly decreased in-cage hyperactivity. Given the behavioral phenotypes and the response to anti-BPD treatments, we propose that MSN mice may provide a possible new model for understanding the neural and genetic basis of phenotypes related to mania and for developing pharmaceutical treatments.
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http://dx.doi.org/10.1016/j.physbeh.2011.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081909PMC
June 2011

Trpc2-deficient lactating mice exhibit altered brain and behavioral responses to bedding stimuli.

Behav Brain Res 2011 Mar 9;217(2):347-53. Epub 2010 Nov 9.

Department of Zoology, University of Wisconsin, Madison, WI, USA.

The trpc2 gene encodes an ion channel involved in pheromonal detection and is found in the vomeronasal organ. In tprc2(-/-) knockout (KO) mice, maternal aggression (offspring protection) is impaired and brain Fos expression in females in response to a male are reduced. Here we examine in lactating wild-type (WT) and KO mice behavioral and brain responses to different olfactory/pheromonal cues. Consistent with previous studies, KO dams exhibited decreased maternal aggression and nest building, but we also identified deficits in nighttime nursing and increases in pup weight. When exposed to the bedding tests, WT dams typically ignored clean bedding, but buried male-soiled bedding from unfamiliar males. In contrast, KO dams buried both clean and soiled bedding. Differences in brain Fos expression were found between WT and KO mice in response to either no bedding, clean bedding, or soiled bedding. In the accessory olfactory bulb, a site of pheromonal signal processing, KO mice showed suppressed Fos activation in the anterior mitral layer relative to WT mice in response to clean and soiled bedding. However, in the medial and basolateral amygdala, KO mice showed a robust Fos response to bedding, suggesting that regions of the amygdala canonically associated with pheromonal sensing can be active in the brains of KO mice, despite compromised signaling from the vomeronasal organ. Together, these results provide further insights into the complex ways by which pheromonal signaling regulates the brain and behavior of the maternal female.
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http://dx.doi.org/10.1016/j.bbr.2010.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010422PMC
March 2011

GABAA receptor signaling in caudal periaqueductal gray regulates maternal aggression and maternal care in mice.

Behav Brain Res 2010 Dec 8;213(2):230-7. Epub 2010 May 8.

University of Wisconsin, Zoology Department, 1117 West Johnson Street, Madison, WI 53706, USA.

Maternal aggression (maternal defense) is exhibited by lactating females towards intruders and contributes to the protection of offspring. Enhancement of Gamma-Aminobutyric acid (GABA)(A) receptor signaling by benzodiazepines elevates maternal aggression, and we previously found indirect evidence (via c-Fos immunohistochemistry) that caudal periaqueductal gray (cPAG) and lateral septum (LS) could be sites where benzodiazepines increase aggression. We recently found that GABA(A) receptor signaling in LS modulates maternal aggression, and in this study, we tested the hypothesis that GABA(A) receptor signaling in cPAG also regulates this behavior. Site-directed injections to cPAG were made in lactating mice using the GABA(A) receptor antagonist, bicuculline (3-9 ng) or the GABA(A) receptor positive modulator, chlordiazepoxide (CDP), a benzodiazepine (2.5-20 microg). Maternal aggression, other maternal behaviors, and anxiety-like measures (using the light-dark box) were then examined. GABA(A) receptor positive modulator did not increase aggression, which could have resulted from a ceiling effect. However, 8 ng and 9 ng of bicuculline in cPAG significantly decreased maternal aggression without altering other maternal behaviors or light-dark box performance, suggesting some GABA(A) receptor signaling in cPAG is required for full maternal aggression expression. Additionally, 7 ng of bicuculline significantly increased licking/grooming of pups, and decreased the number of transitions between the light and dark compartments of the light-dark box without affecting aggression. Given these results indicating that antagonizing GABA(A) receptor in cPAG dose-dependently promotes offspring grooming behavior while impairing aggression, it is possible that the cPAG represents a key site for decision making (aggression versus other behaviors) in the lactating female.
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http://dx.doi.org/10.1016/j.bbr.2010.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918637PMC
December 2010

GABA(A) receptor signaling in the lateral septum regulates maternal aggression in mice.

Behav Neurosci 2009 Dec;123(6):1169-77

Department of Zoology, University of Wisconsin, Madison, Wisconsin 53706, USA.

Maternal aggression (maternal defense) is a fierce aggression produced by lactating females toward intruders that plays an important role in protection of vulnerable offspring. Enhancement of GABA(A) receptor signaling by benzodiazepines increases maternal aggression, and we recently found indirect evidence that lateral septum (LS) could be a key site where benzodiazepines elevate aggression. In this study, we directly tested the hypothesis that activation of GABA(A) receptors in LS would promote maternal aggression while inhibition of this receptor would decrease aggression. Site-directed injections to LS were made using the GABA(A) receptor antagonist, bicuculline (3-30 ng), or the GABA(A) receptor agonists, chlordiazepoxide, a benzodiazepine (2.5-5 microg), and muscimol (0.05-5 ng). Maternal aggression and other behavioral measures were then evaluated in lactating mice. Neither GABA(A) receptor agonist elevated aggression, which could reflect a ceiling effect. However, 7 ng of the GABA(A) receptor antagonist, bicuculline, in LS significantly decreased maternal aggression without altering other maternal behaviors or light-dark box performance, suggesting some GABA(A) receptor signaling in LS is required for full maternal aggression expression. Together, these results confirm a role for GABA(A) receptor signaling in LS in the regulation of maternal aggression.
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http://dx.doi.org/10.1037/a0017535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829870PMC
December 2009
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