Publications by authors named "Donald Pfaff"

189 Publications

Fish as a model in social neuroscience: conservation and diversity in the social brain network.

Biol Rev Camb Philos Soc 2021 Jun 9;96(3):999-1020. Epub 2021 Feb 9.

Brain Research Institute, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor, 47500, Malaysia.

Mechanisms for fish social behaviours involve a social brain network (SBN) which is evolutionarily conserved among vertebrates. However, considerable diversity is observed in the actual behaviour patterns amongst nearly 30000 fish species. The huge variation found in socio-sexual behaviours and strategies is likely generated by a morphologically and genetically well-conserved small forebrain system. Hence, teleost fish provide a useful model to study the fundamental mechanisms underlying social brain functions. Herein we review the foundations underlying fish social behaviours including sensory, hormonal, molecular and neuroanatomical features. Gonadotropin-releasing hormone neurons clearly play important roles, but the participation of vasotocin and isotocin is also highlighted. Genetic investigations of developing fish brain have revealed the molecular complexity of neural development of the SBN. In addition to straightforward social behaviours such as sex and aggression, new experiments have revealed higher order and unique phenomena such as social eavesdropping and social buffering in fish. Finally, observations interpreted as 'collective cognition' in fish can likely be explained by careful observation of sensory determinants and analyses using the dynamics of quantitative scaling. Understanding of the functions of the SBN in fish provide clues for understanding the origin and evolution of higher social functions in vertebrates.
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http://dx.doi.org/10.1111/brv.12689DOI Listing
June 2021

Equation representing the dark-entrained transition from inaction to action in male and female mice.

Behav Brain Res 2020 08 30;392:112673. Epub 2020 May 30.

Laboratory of Neurobiology and Behavior, United States. Electronic address:

The activation of behaviour in a daily rhythm governed by the light cycle is a universal phenomenon among humans, laboratory mammals and other vertebrates. For mice, the active period is during the dark. We have quantified the increase in activity when the lights shut off (Light to Dark, L to D) using a generalized CNS arousal assay with 20 ms resolution, rather than traditional running wheels. Data analysis yielded the rare demonstration of an equation which precisely tracks this behavioural transition and, surprisingly, its reverse during D to L. This behavioural dynamic survives in constant darkness (experiment 2) and is hormone-sensitive (experiment 3). Finally (experiment 4), mice on a light schedule analogous to one which proved troublesome for U.S. Navy sailors, had dysregulated activity bursts which did not conform to the transitions between D and L. These experiments show the lawfulness of a behavioural phase transition and the consequence of deviating from that dynamic pattern. And, in a new way, they bring mathematics to the realm of behavioural neuroscience.
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http://dx.doi.org/10.1016/j.bbr.2020.112673DOI Listing
August 2020

Triphenyl phosphate permeates the blood brain barrier and induces neurotoxicity in mouse brain.

Chemosphere 2020 Aug 16;252:126470. Epub 2020 Mar 16.

School of Public Health, Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, Guangdong, 523-808, China. Electronic address:

Concerns have been raised over the neurotoxicity of triphenyl phosphate (TPP), but there have been few studies of the neurotoxic effects of TPP on mammals and the underlying mechanisms. In this study, weaned male mice (C57/BL6) were used and exposed to 0, 50, or 150 mg/kg TPP daily by oral gavage for 30 days. The blood brain barrier (BBB) permeability of TPP and its metabolite diphenyl phosphate (DPP) in the brain, and TPP induced metabolomic and transcriptomic changes of the brain were investigated. The results showed that TPP and DPP can cross the BBB of mice. Histopathological examination of the brain revealed abnormalities in the hippocampus, cortex and thalamus, and mice treated with high doses showed a potential inflammation in the thalamus and hippocampus. Untargeted metabolomic results revealed that the changed level of glutamic acid, N-acetyl CoA metabolites, and organic acid in the brain of treated mice, suggest that amino acid and lipid metabolism was interfered. RNA-seq data indicated that neuronal transcription processes and cell apoptosis pathway (forkhead box (FOXO), and mitogen-activated protein kinase (MAPK) signaling pathways) were significantly affected by TPP exposure. RT-PCR showed proinflammation cytokine tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6)) levels were increased, while antioxidant genes including nuclear factor-E2-related factor 2 (Nrf2), heme oxygenase1 (HO-1) and superoxide dismutase (SOD1) decreased. These results suggest that TPP could cause a degree of neurotoxicity by inducing neuroinflammation and neuronal apoptosis, which are related to oxidative stress. The potential implications for neurophysiology and behavioral regulation cannot be ignored.
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http://dx.doi.org/10.1016/j.chemosphere.2020.126470DOI Listing
August 2020

Sexual motivation: problem solved and new problems introduced.

Horm Mol Biol Clin Investig 2020 Jan 11;41(2). Epub 2020 Jan 11.

Consultant to Medical Affairs Men's Health/Andrology, Bayer AG, Berlin, Muellerstr. 178, 13353 Berlin, Germany.

Background During the past 50 years, motivational studies have evolved from the logical inference of logically required "intervening variables" to explain behavioral change, to electrophysiological and molecular analyses of the mechanisms causing such changes. Aim The purpose of this review article is two-fold: first to describe the logic of sexual motivation in a way that applies to laboratory animals as well as humans, and the second is to address some of the problems of sexual motivation experienced by men. Results When problems of motivational mechanisms are stripped down to their essentials, as performed in the laboratory animal models and are available for reductionistic studies, then the problems can be solved with certainty, as illustrated in the first part of this review. However, with respect to human sexual motivation, the various determinants which include so many behavioral routes and so many brain states come into play, that definite conclusions are harder to come by, as illustrated in the second part of this review. Conclusions This review highlights a number of key questions that merit further investigation. These include (a) What mechanisms do cultural and experiential influences interact with androgenic hormone influences on human sexual motivation? (b) How would epigenetic effects in the human brain related to changes in motivation be investigated? (c) What are the effects of unpredictable traumatic and stressful human experiences on sexual motivation; (d) How such mechanisms are activated upon unpredictable traumatic and stressful insults? (e) What are the outstanding differences between sexual motivational drive and motivations driven by homeostatic systems such as hunger and thirst?
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http://dx.doi.org/10.1515/hmbci-2019-0055DOI Listing
January 2020

Maternal diabetes induces autism-like behavior by hyperglycemia-mediated persistent oxidative stress and suppression of superoxide dismutase 2.

Proc Natl Acad Sci U S A 2019 11 4;116(47):23743-23752. Epub 2019 Nov 4.

Joint Center of Translational Precision Medicine, Guangzhou Institute of Pediatrics, Guangzhou Women and Children Medical Center, 510623 Guangzhou, China;

Epidemiological studies show that maternal diabetes is associated with an increased risk of autism spectrum disorders (ASDs), although the detailed mechanisms remain unclear. The present study aims to investigate the potential effect of maternal diabetes on autism-like behavior in offspring. The results of in vitro study showed that transient hyperglycemia induces persistent reactive oxygen species (ROS) generation with suppressed superoxide dismutase 2 (SOD2) expression. Additionally, we found that SOD2 suppression is due to oxidative stress-mediated histone methylation and the subsequent dissociation of early growth response 1 (Egr1) on the SOD2 promoter. Furthermore, in vivo rat experiments showed that maternal diabetes induces SOD2 suppression in the amygdala, resulting in autism-like behavior in offspring. SOD2 overexpression restores, while SOD2 knockdown mimics, this effect, indicating that oxidative stress and SOD2 expression play important roles in maternal diabetes-induced autism-like behavior in offspring, while prenatal and postnatal treatment using antioxidants permeable to the blood-brain barrier partly ameliorated this effect. We conclude that maternal diabetes induces autism-like behavior through hyperglycemia-mediated persistent oxidative stress and SOD2 suppression. Here we report a potential mechanism for maternal diabetes-induced ASD.
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http://dx.doi.org/10.1073/pnas.1912625116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876200PMC
November 2019

Hindbrain V2a Neurons Pattern Rhythmic Activity of Motor Neurons in a Reticulospinal Coculture.

Front Neurosci 2019 17;13:1077. Epub 2019 Oct 17.

Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY, United States.

As the capacity to isolate distinct neuronal cell types has advanced over the past several decades, new two- and three-dimensional models of the interactions between different brain regions have expanded our understanding of human neurobiology and the origins of disease. These cultures develop distinctive patterns of activity, but the extent that these patterns are determined by the molecular identity of individual cell types versus the specific pattern of network connectivity is unclear. To address the question of how individual cell types interact , we developed a simplified culture using two excitatory neuronal subtypes known to participate in the reticulospinal circuit: HB9 spinal motor neurons and Chx10 hindbrain V2a neurons. Here, we report the emergence of cell type-specific patterns of activity in culture; on their own, Chx10 neurons developed regular, synchronized bursts of activity that recruited neurons across the entire culture, whereas HB9 neuron activity consisted of an irregular pattern. When these two subtypes were cocultured, HB9 neurons developed synchronized network bursts that were precisely correlated with Chx10 neuron activity, thereby recreating an aspect of Chx10 neurons' role in driving motor activity. These bursts were dependent on AMPA receptors. Our results demonstrate that the molecular classification of the neurons comprising networks is a crucial determinant of their activity. It is therefore possible to improve both the reproducibility and the applicability of neurobiological and disease models by carefully controlling the constituent mixtures of neuronal subtypes.
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http://dx.doi.org/10.3389/fnins.2019.01077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811747PMC
October 2019

Mechanisms for the Approach/Avoidance Decision Applied to Autism.

Trends Neurosci 2019 07;42(7):448-457

Neural Systems Laboratory, Boston University, Boston, MA, USA. Electronic address:

As a neurodevelopmental disorder with serious lifelong consequences, autism has received considerable attention from neuroscientists and geneticists. We present a hypothesis of mechanisms plausibly affected during brain development in autism, based on neural pathways that are associated with social behavior and connect the prefrontal cortex (PFC) to the basal ganglia (BG). We consider failure of social approach in autism as a special case of imbalance in the fundamental dichotomy between behavioral approach and avoidance. Differential combinations of genes mutated, differences in the timing of their impact during development, and graded degrees of hormonal influences may help explain the heterogeneity in symptomatology in autism and predominance in boys.
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http://dx.doi.org/10.1016/j.tins.2019.05.002DOI Listing
July 2019

Tinbergen's challenge for the neuroscience of behavior.

Proc Natl Acad Sci U S A 2019 05 29;116(20):9704-9710. Epub 2019 Apr 29.

Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria.

Nobel laureate Nikolaas Tinbergen provided clear criteria for declaring a neuroscience problem solved, criteria which despite the passage of more than 50 years and vastly expanded neuroscience tool kits remain applicable today. Tinbergen said for neuroscientists to claim that a behavior is understood, they must correspondingly understand its () development and its () mechanisms and its () function and its () evolution. Now, all four of these domains represent hotbeds of current experimental work, each using arrays of new techniques which overlap only partly. Thus, as new methodologies come online, from single-nerve-cell RNA sequencing, for example, to smart FISH, large-scale calcium imaging from cortex and deep brain structures, computational ethology, and so on, one person, however smart, cannot master everything. Our response to the likely "fracturing" of neuroscience recognizes the value of ever larger consortia. This response suggests new kinds of problems for () funding and () the fair distribution of credit, especially for younger scientists.
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http://dx.doi.org/10.1073/pnas.1903589116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525541PMC
May 2019

The Feasibility of Encapsulated Embryonic Medullary Reticular Cells to Grow and Differentiate Into Neurons in Functionalized Gelatin-Based Hydrogels.

Front Mater 2018 Jun 28;5. Epub 2018 Jun 28.

Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, United States.

The study of the behavior of embryonic neurons in controlled conditions require methodologies that take advantage of advanced tissue engineering approaches to replicate elements of the developing brain extracellular matrix. We report here a series of experiments that explore the potential of photo-polymerized gelatin hydrogels to culture primary embryonic neurons. We employed large medullary reticular neurons whose activity is essential for brain arousal as well as a library of gelatin hydrogels that span a range of mechanical properties, inclusion of brain-mimetic hyaluronic acid, and adhesion peptides. These hydrogel platforms showed inherent capabilities to sustain neuronal viability and were permissive for neuronal differentiation, resulting in the development of neurite outgrowth under specific conditions. The maturation of embryonic medullary reticular cells took place in the absence of growth factors or other exogenous bioactive molecules. Immunocytochemistry labeling of neuron-specific tubulin confirmed the initiation of neural differentiation. Thus, this methodology provides an important validation for future studies of nerve cell growth and maintenance.
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http://dx.doi.org/10.3389/fmats.2018.00040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345411PMC
June 2018

Molecular profiling of reticular gigantocellularis neurons indicates that eNOS modulates environmentally dependent levels of arousal.

Proc Natl Acad Sci U S A 2018 07 2;115(29):E6900-E6909. Epub 2018 Jul 2.

Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10065;

Neurons of the medullary reticular nucleus gigantocellularis (NGC) and their targets have recently been a focus of research on mechanisms supporting generalized CNS arousal (GA) required for proper cognitive functions. Using the retro-TRAP method, we characterized transcripts enriched in NGC neurons which have projections to the thalamus. The unique expression and activation of the endothelial nitric oxide (eNOS) signaling pathway in these cells and their intimate connections with blood vessels indicate that these neurons exert direct neurovascular coupling. Production of nitric oxide (NO) within eNOS-positive NGC neurons increases after environmental perturbations, indicating a role for eNOS/NO in modulating environmentally appropriate levels of GA. Inhibition of NO production causes dysregulated behavioral arousal after exposure to environmental perturbation. Further, our findings suggest interpretations for associations between psychiatric disorders and mutations in the eNOS locus.
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http://dx.doi.org/10.1073/pnas.1806123115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055192PMC
July 2018

Can distinctly different rapid estrogen actions share a common mechanistic step?

Horm Behav 2018 08 26;104:156-164. Epub 2018 Feb 26.

Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY, United States.

Contribution to Special Issue on Fast effects of steroids. This paper reviews early evidence for the existence of rapid, non-genomic effects of estrogens on neurons, and, further, proposes that these rapid effects are often synergistic with later, genomic effects. Finally, suggestions about potential molecular mechanisms underlying the rapid effects of estrogens are offered. A mechanistic step we propose to be common among rapid estrogenic actions includes membrane ER's binding to histamine, and NMDA receptors and subsequent dimerization, and clustering (respectively) in a manner that enhances histamine and NMDA actions.
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http://dx.doi.org/10.1016/j.yhbeh.2018.02.008DOI Listing
August 2018

Reproducibility and replicability of rodent phenotyping in preclinical studies.

Neurosci Biobehav Rev 2018 04 31;87:218-232. Epub 2018 Jan 31.

Tel Aviv University, Israel.

The scientific community is increasingly concerned with the proportion of published "discoveries" that are not replicated in subsequent studies. The field of rodent behavioral phenotyping was one of the first to raise this concern, and to relate it to other methodological issues: the complex interaction between genotype and environment; the definitions of behavioral constructs; and the use of laboratory mice and rats as model species for investigating human health and disease mechanisms. In January 2015, researchers from various disciplines gathered at Tel Aviv University to discuss these issues. The general consensus was that the issue is prevalent and of concern, and should be addressed at the statistical, methodological and policy levels, but is not so severe as to call into question the validity and the usefulness of model organisms as a whole. Well-organized community efforts, coupled with improved data and metadata sharing, have a key role in identifying specific problems and promoting effective solutions. Replicability is closely related to validity, may affect generalizability and translation of findings, and has important ethical implications.
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http://dx.doi.org/10.1016/j.neubiorev.2018.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071910PMC
April 2018

Building Bridges through Science.

Neuron 2017 Nov;96(4):730-735

The Scripps Research Institute, La Jolla, CA 92037, USA.

Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched "The Science Bridge" initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities.
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http://dx.doi.org/10.1016/j.neuron.2017.09.028DOI Listing
November 2017

Hormone-dependent medial preoptic/lumbar spinal cord/autonomic coordination supporting male sexual behaviors.

Mol Cell Endocrinol 2018 05 31;467:21-30. Epub 2017 Oct 31.

Department of Biology, Boston University, Boston, MA 02215, United States.

Testosterone (T) can act directly through neural androgen receptors (AR) to facilitate male sexual behavior; however, T's metabolites also can play complicated and interesting roles in the control of mating. One metabolite, dihydrotestosterone (DHT) binds to AR with significantly greater affinity than that of T. Is that important behaviorally? Another metabolite, estradiol (E), offers a potential alternative route of facilitating male mating behavior by acting through estradiol receptors (ER). In this review we explore the roles and relative importance of T as well as E and DHT at various levels of the neuroaxis for the activation of male sex behavior in common laboratory animals and, when relevant research findings are available, in man.
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http://dx.doi.org/10.1016/j.mce.2017.10.018DOI Listing
May 2018

Sex-specific gene-environment interactions underlying ASD-like behaviors.

Proc Natl Acad Sci U S A 2017 02 23;114(6):1383-1388. Epub 2017 Jan 23.

Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10065

The male bias in the incidence of autism spectrum disorders (ASDs) is one of the most notable characteristics of this group of neurodevelopmental disorders. The etiology of this sex bias is far from known, but pivotal for understanding the etiology of ASDs in general. Here we investigate whether a "three-hit" (genetic load × environmental factor × sex) theory of autism may help explain the male predominance. We found that LPS-induced maternal immune activation caused male-specific deficits in certain social responses in the contactin-associated protein-like 2 (Cntnap2) mouse model for ASD. The three "hits" had cumulative effects on ultrasonic vocalizations at postnatal day 3. Hits synergistically affected social recognition in adulthood: only mice exposed to all three hits showed deficits in this aspect of social behavior. In brains of the same mice we found a significant three-way interaction on corticotropin-releasing hormone receptor-1 (Crhr1) gene expression, in the left hippocampus specifically, which co-occurred with epigenetic alterations in histone H3 N-terminal lysine 4 trimethylation (H3K4me3) over the Crhr1 promoter. Although it is highly likely that multiple (synergistic) interactions may be at work, change in the expression of genes in the hypothalamic-pituitary-adrenal/stress system (e.g., Crhr1) is one of them. The data provide proof-of-principle that genetic and environmental factors interact to cause sex-specific effects that may help explain the male bias in ASD incidence.
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http://dx.doi.org/10.1073/pnas.1619312114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307430PMC
February 2017

Development of Electrophysiological Properties of Nucleus Gigantocellularis Neurons Correlated with Increased CNS Arousal.

Dev Neurosci 2016 28;38(4):295-310. Epub 2016 Oct 28.

Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, N.Y., USA.

Many types of data have suggested that neurons in the nucleus gigantocellularis (NGC) in the medullary reticular formation are critically important for CNS arousal and behavioral responsiveness. To extend this topic to a developmental framework, whole-cell patch-recorded characteristics of NGC neurons in brainstem slices and measures of arousal-dependent locomotion of postnatal day 3 (P3) to P6 mouse pups were measured and compared. These neuronal characteristics developed in an orderly, statistically significant monotonic manner over the course of P3-P6: (1) proportion of neurons capable of firing action potential (AP) trains, (2) AP amplitude, (3) AP threshold, (4) amplitude of inward and outward currents, (5) amplitude of negative peak currents, and (6) steady state currents (in I-V plot). These measurements reflect the maturation of sodium and certain potassium channels. Similarly, all measures of locomotion, latency to first movement, total locomotion duration, net locomotion distance, and total quiescence time also developed monotonically over P3-P6. Most importantly, electrophysiological and behavioral measures were significantly correlated. Interestingly, the behavioral measures were not correlated with frequency of excitatory postsynaptic currents or the proportion of neurons showing these currents, responses to a battery of neurotransmitter agents, or rapid activating potassium currents (including IA). Considering the results here in the context of a large body of literature on NGC, we hypothesize that the developmental increase in NGC neuronal excitability participates in causing the increased behavioral responsivity during the postnatal period from P3 to P6.
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http://dx.doi.org/10.1159/000449035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127753PMC
January 2018

Phase-Amplitude Coupling in Spontaneous Mouse Behavior.

PLoS One 2016 15;11(9):e0162262. Epub 2016 Sep 15.

Laboratory for Neurobiology and Behavior, The Rockefeller University, New York, New York, United States of America.

The level of activity of many animals including humans rises and falls with a period of ~ 24 hours. The intrinsic biological oscillator that gives rise to this circadian oscillation is driven by a molecular feedback loop with an approximately 24 hour cycle period and is influenced by the environment, most notably the light:dark cycle. In addition to the circadian oscillations, behavior of many animals is influenced by multiple oscillations occurring at faster-ultradian-time scales. These ultradian oscillations are also thought to be driven by feedback loops. While many studies have focused on identifying such ultradian oscillations, less is known about how the ultradian behavioral oscillations interact with each other and with the circadian oscillation. Decoding the coupling among the various physiological oscillators may be important for understanding how they conspire together to regulate the normal activity levels, as well in disease states in which such rhythmic fluctuations in behavior may be disrupted. Here, we use a wavelet-based cross-frequency analysis to show that different oscillations identified in spontaneous mouse behavior are coupled such that the amplitude of oscillations occurring at higher frequencies are modulated by the phase of the slower oscillations. The patterns of these interactions are different among different individuals. Yet this variability is not random. Differences in the pattern of interactions are confined to a low dimensional subspace where different patterns of interactions form clusters. These clusters expose the differences among individuals-males and females are preferentially segregated into different clusters. These sex-specific features of spontaneous behavior were not apparent in the spectra. Thus, our methodology reveals novel aspects of the structure of spontaneous animal behavior that are not observable using conventional methodology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162262PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025157PMC
August 2017

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor.

Proc Natl Acad Sci U S A 2016 08 25;113(32):9099-104. Epub 2016 Jul 25.

Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065;

Glucocorticoids (GCs) are involved in stress and circadian regulation, and produce many actions via the GC receptor (GR), which is classically understood to function as a nuclear transcription factor. However, the nuclear genome is not the only genome in eukaryotic cells. The mitochondria also contain a small circular genome, the mitochondrial DNA (mtDNA), that encodes 13 polypeptides. Recent work has established that, in the brain and other systems, the GR is translocated from the cytosol to the mitochondria and that stress and corticosteroids have a direct influence on mtDNA transcription and mitochondrial physiology. To determine if stress affects mitochondrially transcribed mRNA (mtRNA) expression, we exposed adult male rats to both acute and chronic immobilization stress and examined mtRNA expression using quantitative RT-PCR. We found that acute stress had a main effect on mtRNA expression and that expression of NADH dehydrogenase 1, 3, and 6 (ND-1, ND-3, ND-6) and ATP synthase 6 (ATP-6) genes was significantly down-regulated. Chronic stress induced a significant up-regulation of ND-6 expression. Adrenalectomy abolished acute stress-induced mtRNA regulation, demonstrating GC dependence. ChIP sequencing of GR showed that corticosterone treatment induced a dose-dependent association of the GR with the control region of the mitochondrial genome. These findings demonstrate GR and stress-dependent transcriptional regulation of the mitochondrial genome in vivo and are consistent with previous work linking stress and GCs with changes in the function of brain mitochondria.
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http://dx.doi.org/10.1073/pnas.1602185113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987818PMC
August 2016

Analyses of rapid estrogen actions on rat ventromedial hypothalamic neurons.

Steroids 2016 07 24;111:100-112. Epub 2016 Mar 24.

Laboratory of Neurobiology & Behavior, The Rockefeller University, New York, NY 10065, USA.

Rapid estrogen actions are widely diverse across many cell types. We conducted a series of electrophysiological studies on single rat hypothalamic neurons and found that estradiol (E2) could rapidly and independently potentiate neuronal excitation/depolarizations induced by histamine (HA) and N-Methyl-d-Aspartate (NMDA). Now, the present whole-cell patch study was designed to determine whether E2 potentiates HA and NMDA depolarizations - mediated by distinctly different types of receptors - by the same or by different mechanisms. For this, the actions of HA, NMDA, as well as E2, were investigated first using various ion channel blockers and then by analyzing and comparing their channel activating characteristics. Results indicate that: first, both HA and NMDA depolarize neurons by inhibiting K(+) currents. Second, E2 potentiates both HA and NMDA depolarizations by enhancing the inhibition of K(+) currents, an inhibition caused by the two transmitters. Third, E2 employs the very same mechanism, the enhancement of K(+) current inhibition, thus to rapidly potentiate HA and NMDA depolarizations. These data are of behavioral importance, since the rapid E2 potentiation of depolarization synergizes with nuclear genomic actions of E2 to facilitate lordosis behavior, the primary female-typical reproductive behavior.
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http://dx.doi.org/10.1016/j.steroids.2016.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965276PMC
July 2016

Rapid estrogen actions on ion channels: A survey in search for mechanisms.

Steroids 2016 07 3;111:46-53. Epub 2016 Mar 3.

The Rockefeller University, New York, NY 10065, USA.

A survey of nearly two hundred reports shows that rapid estrogenic actions can be detected across a range of kinds of estrogens, a range of doses, on a wide range of tissue, cell and ion channel types. Striking is the fact that preparations of estrogenic agents that do not permeate the cell membrane almost always mimic the actions of the estrogenic agents that do permeate the membrane. All kinds of estrogens, ranging from natural ones, through receptor modulators, endocrine disruptors, phytoestrogens, agonists, and antagonists to novel G-1 and STX, have been reported to be effective. For actions on specific types of ion channels, the possibility of opposing actions, in different cases, is the rule, not the exception. With this variety there is no single, specific action mechanism for estrogens per se, although in some cases estrogens can act directly or via some signaling pathways to affect ion channels. We infer that estrogens can bind a large number of substrates/receptors at the membrane surface. As against the variety of subsequent routes of action, this initial step of the estrogen's binding action is the key.
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http://dx.doi.org/10.1016/j.steroids.2016.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929851PMC
July 2016

Implications of Epigenetic Variability within a Cell Population for "Cell Type" Classification.

Front Behav Neurosci 2015 16;9:342. Epub 2015 Dec 16.

Laboratory of Neurobiology and Behavior, The Rockefeller University New York, NY, USA.

Here, we propose a new approach to defining nerve "cell types" in reaction to recent advances in single cell analysis. Among cells previously thought to be equivalent, considerable differences in global gene expression and biased tendencies among differing developmental fates have been demonstrated within multiple lineages. The model of classifying cells into distinct types thus has to be revised to account for this intrinsic variability. A "cell type" could be a group of cells that possess similar, but not necessarily identical properties, variable within a spectrum of epigenetic adjustments that permit its developmental path toward a specific function to be achieved. Thus, the definition of a cell type is becoming more similar to the definition of a species: sharing essential properties with other members of its group, but permitting a certain amount of deviation in aspects that do not seriously impact function. This approach accommodates, even embraces the spectrum of natural variation found in various cell populations and consequently avoids the fallacy of false equivalence. For example, developing neurons will react to their microenvironments with epigenetic changes resulting in slight changes in gene expression and morphology. Addressing the new questions implied here will have significant implications for developmental neurobiology.
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http://dx.doi.org/10.3389/fnbeh.2015.00342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679859PMC
January 2016

Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements.

Proc Natl Acad Sci U S A 2015 Dec 10;112(52):16018-23. Epub 2015 Dec 10.

Department of Psychology, University of Guelph, Guelph, ON, Canada N1G 2W1; Neuroscience Program, University of Guelph, Guelph, ON, Canada N1G 2W1;

Dramatic increases in hippocampal spine synapse density are known to occur within minutes of estrogen exposure. Until now, it has been assumed that enhanced spinogenesis increased excitatory input received by the CA1 pyramidal neurons, but how this facilitated learning and memory was unclear. Delivery of 17β-estradiol or an estrogen receptor (ER)-α (but not ER-β) agonist into the dorsal hippocampus rapidly improved general discrimination learning in female mice. The same treatments increased CA1 dendritic spines in hippocampal sections over a time course consistent with the learning acquisition phase. Surprisingly, estrogen-activated spinogenesis was associated with a decrease in CA1 hippocampal excitatory input, rapidly and transiently reducing CA1 AMPA activity via a mechanism likely reflecting AMPA receptor internalization and creation of silent or immature synapses. We propose that estrogens promote hippocampally mediated learning via a mechanism resembling some of the broad features of normal development, an initial overproduction of functionally immature connections being subsequently "pruned" by experience.
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http://dx.doi.org/10.1073/pnas.1522150112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703013PMC
December 2015

Sexual Motivation in the Female and Its Opposition by Stress.

Curr Top Behav Neurosci 2016 ;27:35-49

Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY, USA.

A well worked-out motivational system in laboratory animals produces estrogen-dependent female sex behavior. Here, we review (a) the logical definition of sexual motivation and (b) the basic neuronal and molecular mechanisms that allow the behavior to occur. Importantly, reproductive mechanisms in the female can be inhibited by stress. This is interesting because, in terms of the specificity of neuroendocrine dynamics in space and time, the two families of phenomena, sex and stress, are the opposite of each other. We cover papers that document stress effects on the underlying processes of reproductive endocrinology in the female. Not all of the mechanisms for such inhibition have been clearly laid out. Finally, as a current topic of investigation, this system offers several avenues for new investigation which we briefly characterize.
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http://dx.doi.org/10.1007/7854_2015_392DOI Listing
July 2016

Silencing Estrogen Receptor-α with siRNA in the Intact Rodent Brain.

Methods Mol Biol 2016 ;1366:343-352

Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY, USA.

The ability to silence the expression of gene products in a chemically, spatially, and temporally specific manner in the brains of animals has enabled key breakthroughs in the field of behavioral neuroscience. Using this technique, estrogen receptor alpha (ERα) has been specifically implicated in a multitude of behaviors in mice, including sexual, aggressive, locomotor, and maternal behaviors. ERα has been identified in a variety of brain regions, including the medial preoptic area, ventromedial hypothalamus, and amygdala. In this chapter we describe the techniques involved in the generation of the small hairpin RNAs (shRNAs) specifically designed to silence ERα, the construction of the adeno-associated viral (AAV) vector for delivery of the shRNA, the procedures to confirm the silencing of ERα (in vitro and in vivo) and in vivo delivery of the shRNAs to the brains of animals.
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http://dx.doi.org/10.1007/978-1-4939-3127-9_27DOI Listing
August 2016

Estrogens, androgens and generalized behavioral arousal in gonadectomized female and male C57BL/6 mice.

Physiol Behav 2015 Aug 30;147:255-63. Epub 2015 Apr 30.

Department of Psychology, University of Tromsø, 9037 Tromsø, Norway.

General arousal has been operationally defined as an enhanced motor activity and enhanced intensity of response to sensory stimuli. Even though the effects of gonadal hormones on mating behavior have been much studied, their potential effect on generalized arousal, as defined above, has never been evaluated. In the present study we employed a thoroughly validated assay of general arousal to determine the effects of estradiol (E) and testosterone (T) in gonadectomized female and male mice, respectively. The steroids were administered in three different ways: A fast-acting, water soluble preparation given intraperitoneally, an oil solution given subcutaneously, and an oil solution in a subcutaneous Silastic capsule. Motor activity and responses to sensory stimuli were recorded for 24h, 91h, and seven days following hormone administration, respectively. All measures of arousal varied according to the day/night cycle. The water soluble steroid preparation had no reliable effect. When the same doses of estradiol and testosterone were administered subcutaneously in an oil vehicle no effect of either treatment on arousal was observed. The subcutaneously implanted capsule containing estradiol or testosterone had a delayed effect on motor activity in females (four to seven days) but no effect in males. The long time required by the gonadal hormones for affecting arousal would be consistent with, but does not prove, a genomic action. The limited effects of E and T in our arousal assay suggest to us that the strongest actions of these hormones on arousal occur in the context of sequences of responses to sexually relevant stimuli.
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http://dx.doi.org/10.1016/j.physbeh.2015.04.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456673PMC
August 2015

Impact of Thyroid Hormones on Estrogen Receptor α-Dependent Transcriptional Mechanisms in Ventromedial Hypothalamus and Preoptic Area.

Neuroendocrinology 2015 13;101(4):331-46. Epub 2015 Mar 13.

Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, N.Y., USA.

Elevated levels of thyroid hormones (TH) reduce estradiol (E2)-dependent female sexual behavior. E2 stimulates progesterone receptor (Pgr) and oxytocin receptor (Oxtr) within the ventromedial hypothalamus and preoptic area, critical hypothalamic nuclei for sexual and maternal behavior, respectively. Here, we investigated the impact of TH on E2-dependent transcriptional mechanisms in female mice. First, we observed that triiodothyronine (T3) inhibited the E2 induction of Pgr and Oxtr. We hypothesized that differences in histone modifications and receptor recruitment could explain the influence of TH on E2-responsive Pgr and Oxtr expression. We observed that histone H3 acetylation (H3Ac) and methylation (H3K4me3) was gene and brain-region specific. We then analyzed the recruitment of estrogen receptor α (ERα) and TH receptor α (TRα) on the putative regulatory sequences of Pgr and Oxtr. Interestingly, T3 inhibited E2-induced ERα binding to a specific Pgr enhancer site, whereas TRα binding was not affected, corroborating our theory that the competitive binding of TRα to an ERα binding site can inhibit ERα transactivation and the subsequent E2-responsive gene expression. On the Oxtr promoter, E2 and T3 worked together to modulate ERα and TRα binding. Finally, the E2-dependent induction of cofactors was reduced by hypothyroidism and T3. Thus, we determined that the Pgr and Oxtr promoter regions are responsive to E2 and that T3 interferes with the E2 regulation of Pgr and Oxtr expression by altering the recruitment of receptors to DNA and changing the availability of cofactors. Collectively, our findings provide insights into molecular mechanisms of response to E2 and TH interactions controlling sex behavior in the hypothalamus.
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http://dx.doi.org/10.1159/000381459DOI Listing
April 2016

Stochastic modeling of mouse motor activity under deep brain stimulation: the extraction of arousal information.

PLoS Comput Biol 2015 Feb 26;11(2):e1003883. Epub 2015 Feb 26.

Laboratory of Neurobiology and Behavior, Rockefeller University, New York, New York, United States of America.

In the present paper, we quantify, with a rigorous approach, the nature of motor activity in response to Deep Brain Stimulation (DBS), in the mouse. DBS is currently being used in the treatment of a broad range of diseases, but its underlying principles are still unclear. Because mouse movement involves rapidly repeated starting and stopping, one must statistically verify that the movement at a given stimulation time was not just coincidental, endogenously-driven movement. Moreover, the amount of activity changes significantly over the circadian rhythm, and hence the means, variances and autocorrelations are all time varying. A new methodology is presented. For example, to discern what is and what is not impacted by stimulation, velocity is classified (in a time-evolving manner) as being zero-, one- and two-dimensional movement. The most important conclusions of the paper are: (1) (DBS) stimulation is proven to be truly effective; (2) it is two-dimensional (2-D) movement that strongly differs between light and dark and responds to stimulation; and, (3) stimulation in the light initiates a manner of movement, 2-D movement, that is more commonly seen in the (non-stimulated) dark. Based upon these conclusions, it is conjectured that the above patterns of 2-D movement could be a straightforward, easy to calculate correlate of arousal. The above conclusions will aid in the systematic evaluation and understanding of how DBS in CNS arousal pathways leads to the activation of behavior.
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http://dx.doi.org/10.1371/journal.pcbi.1003883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342049PMC
February 2015

Self-assessment of anatomy, sexual sensitivity, and function of the labia and vagina.

Clin Anat 2015 Apr 12;28(3):355-62. Epub 2015 Feb 12.

Pediatric Urology, UPMC Hamot, Erie, Pennsylvania; Pfaff Laboratory of Neurobiology and Behavior, Rockefeller University, New York, New York.

Patient perceptions of genital esthetics are motivating requests for plastic surgeries that could change sexual sensitivity. There is little information about the sensitivities of labial and introital sites. The aim of this study is to assess the relationship between sexual sensitivity and self-reported sizes of labial and introital sites. Sixty-two healthy, sexually active, adult women (mean age 37.9, range 21-60) with no history of genital or vaginal surgery gave written consent to participate in this study. A modified version of Self-Assessment of Genital Anatomy and Sexual Function (L-SAGASF-F) was used to assess labial and introital size. Site-specific sensation was rated on Likert scales of 1-5. Anatomical locations were compared for ratings. Of 62 responders, 84% (52) described their labia as "average-sized," 11% (7) described their labia minora and 13% (8) their labia majora as "large", and 3% (2) and 5% (3) as "small". Sexual pleasure ratings were "moderate" (median value: 3.0 for external genitalia and vaginal lumen) or "strong" (median value: 4.0 for the interior vagina). Significantly higher rankings related to the vaginal opening (P=0.007). Orgasm intensity for stimulation of the external genitalia progressively increased toward the vaginal opening, from 1.0 to 3.0 (P=0.001); vaginal ratings showed a similar progression, from 2.0 at the external luminal margin to 3.0 in the deep interior (P<0.0001). Orgasm effort scores were intermediate (median: 3.0), uniform throughout the external and internal areas (P=0.626). Ratings for labial and introital sensitivity, regardless of self-reported size, were very similar to those at other genital sites for sexual pleasure. Surgical excision of labial and introital structures could modify sexual sensation.
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http://dx.doi.org/10.1002/ca.22503DOI Listing
April 2015