Publications by authors named "Ken Soderstrom"

27 Publications

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CB antagonism increases excitatory synaptogenesis in a cortical spheroid model of fetal brain development.

Sci Rep 2021 Apr 30;11(1):9356. Epub 2021 Apr 30.

Department of Anatomy and Cell Biology, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA.

The endocannabinoid system (ECS) plays a complex role in the development of neural circuitry during fetal brain development. The cannabinoid receptor type 1 (CB) controls synaptic strength at both excitatory and inhibitory synapses and thus contributes to the balance of excitatory and inhibitory signaling. Imbalances in the ratio of excitatory to inhibitory synapses have been implicated in various neuropsychiatric disorders associated with dysregulated central nervous system development including autism spectrum disorder, epilepsy, and schizophrenia. The role of CB in human brain development has been difficult to study but advances in induced pluripotent stem cell technology have allowed us to model the fetal brain environment. Cortical spheroids resemble the cortex of the dorsal telencephalon during mid-fetal gestation and possess functional synapses, spontaneous activity, an astrocyte population, and pseudo-laminar organization. We first characterized the ECS using STORM microscopy and observed synaptic localization of components similar to that which is observed in the fetal brain. Next, using the CB-selective antagonist SR141716A, we observed an increase in excitatory, and to a lesser extent, inhibitory synaptogenesis as measured by confocal image analysis. Further, CB antagonism increased the variability of spontaneous activity within developing neural networks, as measured by microelectrode array. Overall, we have established that cortical spheroids express ECS components and are thus a useful model for exploring endocannabinoid mediation of childhood neuropsychiatric disease.
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http://dx.doi.org/10.1038/s41598-021-88750-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087674PMC
April 2021

Delta-9-THC exposure during zebra finch sensorimotor vocal learning increases cocaine reinforcement in adulthood.

Pharmacol Biochem Behav 2019 10 23;185:172764. Epub 2019 Aug 23.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States of America. Electronic address:

Zebra finches are songbirds that learn vocal patterns during a sensitive period of development that approximates adolescence. Exposure of these animals to a cannabinoid agonist during their period of sensorimotor vocal learning alters song patterns produced in adulthood. Thus, songbirds have unique value in studying developmental effects of drug exposure on a naturally learned behavior. A missing feature of this animal model has been a method to study drug reinforcement of behavior. To address this gap we have adapted place conditioning methods, used previously to determine that singing behavior is rewarding, to study cocaine reinforcement of behavior. We have found that cocaine dose-dependently reinforces both place conditioning and aversion at potencies consistent with those observed in mammalian species. Use of this place conditioning method has allowed us to determine that, when administered during periods of sensorimotor vocal learning, delta-9-THC, but not nicotine persistently increases sensitivity to cocaine through adulthood. Establishment of this method significantly expands the songbird drug exposure model, and holds promise for better appreciation of mechanisms important to sensorimotor learning that is dependent upon successful progress through sensitive periods of CNS development.
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http://dx.doi.org/10.1016/j.pbb.2019.172764DOI Listing
October 2019

Cannabidiol improves vocal learning-dependent recovery from, and reduces magnitude of deficits following, damage to a cortical-like brain region in a songbird pre-clinical animal model.

Neuropharmacology 2019 11 17;158:107716. Epub 2019 Jul 17.

Department of Pharmacology and Toxicology, ECU Brody School of Medicine, Greenville, NC, 27834, USA. Electronic address:

Cannabidiol (CBD), a non-euphorigenic compound derived from Cannabis, shows promise for improving recovery following cerebral ischemia and has recently been shown effective for the treatment of childhood seizures caused by Dravet and Lennox-Gastaut syndromes. Given evidence for activity to mitigate effects of CNS insult and dysfunction, we considered the possibility that CBD may also protect and improve functional recovery of a complex learned behavior. To test this hypothesis, we have applied a songbird, the adult male zebra finch, as a novel pre-clinical animal model. Their learned vocalizations were temporarily disrupted with bilateral microlesions of HVC (used as a proper name) a pre-vocal motor cortical-like brain region that drives song. These microlesions destroy about 10% of HVC, and temporarily impair song production, syntax and phonology for about seven days. Recovery requires sensorimotor learning as it depends upon auditory feedback. Four CBD doses (0, 1, 10 and 100 mg/kg) within three surgery conditions (microlesion, no-microlesion, sham-microlesion) were evaluated (n = 5-6). Birds were recorded over 20 days: three baseline; six pre-microlesion drug treatment days and; 11 post-microlesion treatment and recovery days. Results indicate 10 and 100 mg/kg CBD effectively reduced the time required to recover vocal phonology and syntax. In the case of phonology, the magnitude of microlesion-related disruptions were also reduced. These results suggest CBD holds promise to improve functional recovery of complex learned behaviors following brain injury, and represent establishment of an important new animal model to screen drugs for efficacy to improve vocal recovery.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107716DOI Listing
November 2019

Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms.

Front Pharmacol 2017 10;8:720. Epub 2017 Oct 10.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, United States.

Cannabinoids include the active constituents of or are molecules that mimic the structure and/or function of these -derived molecules. Cannabinoids produce many of their cellular and organ system effects by interacting with the well-characterized CB1 and CB2 receptors. However, it has become clear that not all effects of cannabinoid drugs are attributable to their interaction with CB1 and CB2 receptors. Evidence now demonstrates that cannabinoid agents produce effects by modulating activity of the entire array of cellular macromolecules targeted by other drug classes, including: other receptor types; ion channels; transporters; enzymes, and protein- and non-protein cellular structures. This review summarizes evidence for these interactions in the CNS and in cancer, and is organized according to the cellular targets involved. The CNS represents a well-studied area and cancer is emerging in terms of understanding mechanisms by which cannabinoids modulate their activity. Considering the CNS and cancer together allow identification of non-cannabinoid receptor targets that are shared and divergent in both systems. This comparative approach allows the identified targets to be compared and contrasted, suggesting potential new areas of investigation. It also provides insight into the diverse sources of efficacy employed by this interesting class of drugs. Obtaining a comprehensive understanding of the diverse mechanisms of cannabinoid action may lead to the design and development of therapeutic agents with greater efficacy and specificity for their cellular targets.
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http://dx.doi.org/10.3389/fphar.2017.00720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641363PMC
October 2017

Chronic CB1 cannabinoid receptor antagonism persistently increases dendritic spine densities in brain regions important to zebra finch vocal learning and production in an antidepressant-sensitive manner.

Brain Res 2017 Oct 22;1672:1-9. Epub 2017 Jul 22.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. Electronic address:

During typical late-postnatal CNS development, net reductions in dendritic spine densities are associated with activity-dependent learning. Prior results showed agonist exposure in young animals increased spine densities in a subset of song regions while adult exposures did not, suggesting endocannabinoid signaling regulates dendritic spine dynamics important to vocal development. Here we addressed this question using the CB1 receptor-selective antagonist SR141716A (SR) to disrupt endocannabinoid signaling both during and after vocal learning. We hypothesized antagonist exposure during vocal development, but not adulthood, would alter spine densities. Following 25days of exposure and a 25day maturation period, 3D reconstructions of Golgi-Cox stained neurons were used to measure spine densities. We found antagonist treatments during both age periods increased densities within Area X (basal ganglia) and following adult treatments within HVC (premotor cortical-like). Results suggest both inappropriate cannabinoid receptor stimulation and inhibition are capable of similar disregulatory effects during establishment of circuits important to vocal learning, with antagonism extending these effects through adulthood. Given clinical evidence of depressant effects of SR, we tested the ability of the antidepressant monoamine oxidase inhibitor (MAOI) phenelzine to mitigate SR-induced spine density increases. This was confirmed implicating interaction between monoamine and endocannabinoid systems. Finally, we evaluated acute effects of these drugs to alter ability of novel song exposure to increase spine densities in auditory NCM and other regions, finding when combined, SR and phenelzine increased densities within Area X. These results contribute to understanding relevance of dendritic spine dynamics in neuronal development, drug abuse, and depression.
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http://dx.doi.org/10.1016/j.brainres.2017.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661891PMC
October 2017

Developmental but not adult cannabinoid treatments persistently alter axonal and dendritic morphology within brain regions important for zebra finch vocal learning.

Brain Res 2014 Apr 2;1558:57-73. Epub 2014 Mar 2.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States. Electronic address:

Prior work shows developmental cannabinoid exposure alters zebra finch vocal development in a manner associated with altered CNS physiology, including changes in patterns of CB1 receptor immunoreactivity, endocannabinoid concentrations and dendritic spine densities. These results raise questions about the selectivity of developmental cannabinoid effects: are they a consequence of a generalized developmental disruption, or are effects produced through more selective and distinct interactions with biochemical pathways that control receptor, endogenous ligand and dendritic spine dynamics? To begin to address this question we have examined effects of developmental cannabinoid exposure on the pattern and density of expression of proteins critical to dendritic (MAP2) and axonal (Nf-200) structure to determine the extent to which dendritic vs. axonal neuronal morphology may be altered. Results demonstrate developmental, but not adult cannabinoid treatments produce generalized changes in expression of both dendritic and axonal cytoskeletal proteins within brain regions and cells known to express CB1 cannabinoid receptors. Results clearly demonstrate that cannabinoid exposure during a period of sensorimotor development, but not adulthood, produce profound effects upon both dendritic and axonal morphology that persist through at least early adulthood. These findings suggest an ability of exogenous cannabinoids to alter general processes responsible for normal brain development. Results also further implicate the importance of endocannabinoid signaling to peri-pubertal periods of adolescence, and underscore potential consequences of cannabinoid abuse during periods of late-postnatal CNS development.
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http://dx.doi.org/10.1016/j.brainres.2014.02.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017900PMC
April 2014

Developmental pattern of diacylglycerol lipase-α (DAGLα) immunoreactivity in brain regions important for song learning and control in the zebra finch (Taeniopygia guttata).

J Chem Neuroanat 2013 Nov 17;53:41-59. Epub 2013 Oct 17.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States. Electronic address:

Zebra finch song is a learned behavior dependent upon successful progress through a sensitive period of late-postnatal development. This learning is associated with maturation of distinct brain nuclei and the fiber tract interconnections between them. We have previously found remarkably distinct and dense CB1 cannabinoid receptor expression within many of these song control brain regions, implying a normal role for endocannabinoid signaling in vocal learning. Activation of CB1 receptors via daily treatments with exogenous agonist during sensorimotor stages of song learning (but not in adulthood) results in persistent alteration of song patterns. Now we are working to understand physiological changes responsible for this cannabinoid-altered vocal learning. We have found that song-altering developmental treatments are associated with changes in expression of endocannabinoid signaling elements, including CB1 receptors and the principal CNS endogenous agonist, 2-AG. Within CNS, 2-AG is produced largely through activity of the α isoform of the enzyme diacylglycerol lipase (DAGLα). To better appreciate the role of 2-AG production in normal vocal development we have determined the spatial distribution of DAGLα expression within zebra finch CNS during vocal development. Early during vocal development at 25 days, DAGLα staining is typically light and of fibroid processes. Staining peaks late in the sensorimotor stage of song learning at 75 days and is characterized by fiber, neuropil and some staining of both small and large cell somata. Results provide insight to the normal role for endocannabinoid signaling in the maturation of brain regions responsible for song learning and vocal-motor output, and suggest mechanisms by which exogenous cannabinoid exposure alters acquisition of this form of vocal communication.
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http://dx.doi.org/10.1016/j.jchemneu.2013.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856710PMC
November 2013

Novel song-stimulated dendritic spine formation and Arc/Arg3.1 expression in zebra finch auditory telencephalon are disrupted by cannabinoid agonism.

Brain Res 2013 Dec 14;1541:9-21. Epub 2013 Oct 14.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

Cannabinoids are well-established to alter processes of sensory perception; however neurophysiological mechanisms responsible remain unclear. Arc, an immediate-early gene (IEG) product involved in dendritic spine dynamics and necessary for plasticity changes such as long-term potentiation, is rapidly induced within zebra finch caudal medial nidopallium (NCM) following novel song exposure, a response that habituates after repeated stimuli. Arc appears unique in its rapid postsynaptic dendritic expression following excitatory input. Previously, we found that vocal development-altering cannabinoid treatments are associated with elevated dendritic spine densities in motor-(HVC) and learning-related (Area X) song regions of zebra finch telencephalon. Given Arc's dendritic morphological role, we hypothesized that cannabinoid-altered spine densities may involve Arc-related signaling. To test this, we examined the ability of the cannabinoid agonist WIN55212-2 (WIN) to (1) acutely disrupt song-induced Arc expression, (2) interfere with habituation to auditory stimuli, and (3) alter dendritic spine densities in auditory regions. We found that WIN (3mg/kg) acutely reduced Arc expression within both NCM and Field L2 in an antagonist-reversible manner. WIN did not alter Arc expression in thalamic auditory relay nucleus ovoidalis (Ov), suggesting that cannabinoid signaling selectively alters responses to auditory stimulation. Novel song stimulation rapidly increased dendritic spine densities within auditory telencephalon, an effect blocked by WIN pretreatments. Taken together, cannabinoid inhibition of both Arc induction and its habituation to repeated stimuli, combined with prevention of rapid increases in dendritic spine densities, implicates cannabinoid signaling in modulation of physiological processes important to auditory responsiveness and memory.
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http://dx.doi.org/10.1016/j.brainres.2013.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891467PMC
December 2013

Cannabinoid mitigation of neuronal morphological change important to development and learning: insight from a zebra finch model of psychopharmacology.

Life Sci 2013 Mar 1;92(8-9):467-75. Epub 2012 Aug 1.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

Normal CNS development proceeds through late-postnatal stages of adolescent development. The activity-dependence of this development underscores the significance of CNS-active drug exposure prior to completion of brain maturation. Exogenous modulation of signaling important in regulating normal development is of particular concern. This mini-review presents a summary of the accumulated behavioral, physiological and biochemical evidence supporting such a key regulatory role for endocannabinoid signaling during late-postnatal CNS development. Our focus is on the data obtained using a unique zebra finch model of developmental psychopharmacology. This animal has allowed investigation of neuronal morphological effects essential to establishment and maintenance of neural circuitry, including processes related to synaptogenesis and dendritic spine dynamics. Altered neurophysiology that follows exogenous cannabinoid exposure during adolescent development has the potential to persistently alter cognition, learning and memory.
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http://dx.doi.org/10.1016/j.lfs.2012.07.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756909PMC
March 2013

Altered patterns of filopodia production in CHO cells heterologously expressing zebra finch CB(1) cannabinoid receptors.

Cell Adh Migr 2012 Mar-Apr;6(2):91-9. Epub 2012 Mar 1.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.

Recent findings indicate that cannabinoid-altered vocal development involves elevated densities of dendritic spines in a subset of brain regions involved in zebra finch song learning and production suggesting that cannabinoid receptor activation may regulate cell structure. Here we report that activation of zebra finch CB 1 receptors (zfCB 1, delivered by a lentivector to CHO cells) produces dose-dependent biphasic effects on the mean length of filopodia expressed: Low agonist concentrations (3 nM WIN55212-2) increase lengths while higher concentrations reduce them. In contrast, treatment of zfCB 1-expressing cells with the antagonist/inverse agonist SR141716A causes increases in both mean filopodia length and number at 30 and 100 nM. These results demonstrate that CB 1 receptor activation can differentially influence filiopodia elongation depending on dose, and demonstrate that manipulation of cannabinoid receptor activity is capable of modulating cell morphology.
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http://dx.doi.org/10.4161/cam.20164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499318PMC
November 2012

Late-postnatal cannabinoid exposure persistently elevates dendritic spine densities in area X and HVC song regions of zebra finch telencephalon.

Brain Res 2011 Aug 17;1405:23-30. Epub 2011 Jun 17.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

Centrally acting cannabinoids are well known for their ability to impair functions associated with both learning and memory but appreciation of the physiological mechanisms underlying these actions, particularly those that persist, remains incomplete. Our earlier studies have shown that song stereotypy is persistently reduced in male zebra finches that have been developmentally exposed to cannabinoids. In the present work, we examined the extent to which changes in neuronal morphology (dendritic spine densities and soma size) within brain regions associated with zebra finch vocal learning are affected by late-postnatal cannabinoid agonist exposure. We found that daily treatment with the cannabinoid agonist WIN55212-2 (WIN, 1mg/kg IM) is associated with 27% and 31% elevations in dendritic spine densities in the song regions Area X and HVC, respectively. We also found an overall increase in cell diameter within HVC. Changes in dendritic spine densities were only produced following developmental exposure; treatments given to adults that had completed vocal learning were not effective. These findings have important implications for understanding how repeated cannabinoid exposure can produce significant, lasting alteration of brain morphology, which may contribute to altered development and behavior.
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http://dx.doi.org/10.1016/j.brainres.2011.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428047PMC
August 2011

Cannabinoid exposure during zebra finch sensorimotor vocal learning persistently alters expression of endocannabinoid signaling elements and acute agonist responsiveness.

BMC Neurosci 2011 Jan 6;12. Epub 2011 Jan 6.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

Background: Previously we have found that cannabinoid treatment of zebra finches during sensorimotor stages of vocal development alters song patterns produced in adulthood. Such persistently altered behavior must be attributable to changes in physiological substrates responsible for song. We are currently working to identify the nature of such physiological changes, and to understand how they contribute to altered vocal learning. One possibility is that developmental agonist exposure results in altered expression of elements of endocannabinoid signaling systems. To test this hypothesis we have studied effects of the potent cannabinoid receptor agonist WIN55212-2 (WIN) on endocannabinoid levels and densities of CB1 immunostaining in zebra finch brain.

Results: We found that late postnatal WIN treatment caused a long-term global disregulation of both levels of the endocannabinoid, 2-arachidonyl glycerol (2-AG) and densities of CB1 immunostaining across brain regions, while repeated cannabinoid treatment in adults produced few long-term changes in the endogenous cannabinoid system.

Conclusions: Our findings indicate that the zebra finch endocannabinoid system is particularly sensitive to exogenous agonist exposure during the critical period of song learning and provide insight into susceptible brain areas.
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http://dx.doi.org/10.1186/1471-2202-12-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025904PMC
January 2011

Role of mouse cerebellar nicotinic acetylcholine receptor (nAChR) α(4)β(2)- and α(7) subtypes in the behavioral cross-tolerance between nicotine and ethanol-induced ataxia.

Behav Brain Res 2011 Mar 23;217(2):282-92. Epub 2010 Oct 23.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

We have demonstrated that nicotine attenuated ethanol-induced ataxia via nicotinic-acetylcholine-receptor (nAChR) subtypes α(4)β(2) and α(7). In the present study, ethanol (2g/kg; i.p.)-induced ataxia was assessed by Rotorod performance following repeated intracerebellar infusion of α(4)β(2)- and α(7)-selective agonists. Localization of α(4)β(2) and α(7) nAChRs was confirmed immunohistochemically. Cerebellar NO(x) (nitrite+nitrate) was determined flurometrically. Repeated intracerebellar microinfusion of the α(4)β(2)-selective agonist, RJR-2403 (for 1, 2, 3, 5 or 7 days) or the α(7)-selective agonist, PNU-282987 (1, 2, 3 or 5 days), dose-dependently attenuated ethanol-induced ataxia. These results suggest the development of cross-tolerance between ethanol-induced ataxia and α(4)β(2) and α(7) nAChR agonists. With RJR-2403, the cross-tolerance was maximal after a 5-day treatment and lasted 48h. Cross-tolerance was maximal after a 1-day treatment with PNU-282987 and lasted 72h. Pretreatment with α(4)β(2)- and α(7)-selective antagonists, dihydro-β-erythroidine and methyllycaconitine, respectively, prevented the development of cross-tolerance confirming α(4)β(2) and α(7) involvement. Repeated agonist infusions elevated cerebellar NO(x) 16h after the last treatment while acute ethanol exposure decreased it. Pretreatment with repeated RJR-2403 or PNU-282987 reversed ethanol-induced decrease in NOx. The NO(x) data suggests the involvement of the nitric oxide (NO)-cGMP signaling pathway in the cross-tolerance that develops between α(4)β(2)- and α(7)-selective agonists and ethanol ataxia. Both α(4)β(2) and α(7) subtypes exhibited high immunoreactivity in Purkinje but sparse expression in molecular and granular cell layers. Our results support a role for α(4)β(2) and α(7) nAChR subtypes in the development of cross-tolerance between nicotine and ethanol with the NO signaling pathway as a potential mechanism.
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http://dx.doi.org/10.1016/j.bbr.2010.10.026DOI Listing
March 2011

Late-postnatal cannabinoid exposure persistently increases FoxP2 expression within zebra finch striatum.

Dev Neurobiol 2010 Feb;70(3):195-203

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA.

Prior work has shown that cannabinoid exposure of zebra finches during sensorimotor stages of vocal development alters song patterns produced in adulthood. We are currently working to identify physiological substrates for this altered song learning. FoxP2 is a transcription factor associated with altered vocal development in both zebra finches and humans. This protein shows a distinct pattern of expression within Area X of striatum that coincides with peak expression of CB(1) cannabinoid receptors during sensorimotor learning. Coincident expression in a brain region essential for song learning led us to test for a potential signaling interaction. We have found that cannabinoid agonists acutely increase expression of FoxP2 throughout striatum. When administered during sensorimotor song learning, cannabinoids increase basal levels of striatal FoxP2 expression in adulthood. Thus, song-altering cannabinoid treatments are associated with persistent increases in basal expression of FoxP2 in zebra finch striatum.
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http://dx.doi.org/10.1002/dneu.20772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907664PMC
February 2010

Lessons from nonmammalian species.

Authors:
Ken Soderstrom

Curr Top Behav Neurosci 2009 ;1:173-98

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

There is abundant evidence for the presence of endogenous cannabinoid signaling systems in many nonmammalian species, including several classes of invertebrates. Interest in the study of these animals largely relates to their production of distinct and measurable specialized behaviors. The ability to alter these behaviors through manipulation of cannabinoid signaling has provided important insight into both the phylogenetic history and physiological relevance of this essential neuromodulatory system.This chapter presents a review of literature relevant to cannabinoid-altered behaviors in nonmammalian species from insects through advanced vocal learning avian species. Integration of findings supports a common role for endocannabinoid (ECB) modulation of ingestive and locomotor behaviors, with interesting contrasting agonist effects that distinguish vertebrate and invertebrate classes. Studies in amphibians and birds suggest that ECB signaling may function as a behavioral switch, allowing redirection from less- to more-essential behaviors in response to emergent environmental changes. Overall, the studies provide evidence for cannabinoid modulation of aggression, emesis, feeding behavior, locomotor activity, reproductive behaviors, vocal learning, sensory perception and stress responses.
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http://dx.doi.org/10.1007/978-3-540-88955-7_7DOI Listing
January 2011

CB(1) cannabinoid receptor activation dose dependently modulates neuronal activity within caudal but not rostral song control regions of adult zebra finch telencephalon.

Psychopharmacology (Berl) 2008 Aug 29;199(2):265-73. Epub 2008 May 29.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

Rationale: CB(1) cannabinoid receptors are distinctly expressed at high density within several regions of zebra finch telencephalon, including those known to be involved in song learning (lMAN and Area X) and production (HVC and RA) because (1) exposure to cannabinoid agonists during developmental periods of auditory and sensory-motor song learning alters song patterns produced later in adulthood and (2) densities of song region expression of CB(1) waxes and wanes during song learning. It is becoming clear that CB(1)-receptor-mediated signaling is important to normal processes of vocal development.

Materials And Methods: To better understand the mechanisms involved in cannabinoid modulation of vocal behavior, we have investigated the dose-response relationship between systemic cannabinoid exposure and changes in neuronal activity (as indicated by expression of the transcription factor, c-Fos) within telencephalic brain regions, with established involvement in song learning and/or control.

Results: In adults, we have found that low doses (0.1 mg/kg) of the cannabinoid agonist WIN-55212-2 decrease neuronal activity (as indicated by densities of c-fos-expressing nuclei) within vocal motor regions of caudal telencephalon (HVC and RA) while higher doses (3 mg/kg) stimulate activity. Both effects were reversed by pretreatment with the CB(1)-selective antagonist rimonabant. Interestingly, no effects of cannabinoid treatment were observed within the rostral song regions lMAN and Area X, despite distinct and dense CB(1) receptor expression within these areas.

Conclusions: Overall, our results demonstrate that, depending on dosage, CB(1) agonism can both inhibit and stimulate neuronal activity within brain regions controlling adult vocal motor output, implicating involvement of multiple CB(1)-sensitive neuronal circuits.
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http://dx.doi.org/10.1007/s00213-008-1190-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2586593PMC
August 2008

A minimally invasive procedure for sexing young zebra finches.

J Neurosci Methods 2007 Aug 18;164(1):116-9. Epub 2007 Apr 18.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

Zebra finches have been widely used to study neurobiology underlying vocal development. Because only male zebra finches learn song, efficient developmental use of these animals requires early determination of sex at ages that precede maturation of secondary sex characteristics. We have developed a sex determination method that combines a forensics method of genomic DNA isolation (from very small blood samples) with PCR amplification from Z and W sex chromosomes (males are ZZ, females ZW). This combination results in a minimally invasive yet highly reliable and convenient genotyping method.
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http://dx.doi.org/10.1016/j.jneumeth.2007.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2350111PMC
August 2007

Nicotine increases FosB expression within a subset of reward- and memory-related brain regions during both peri- and post-adolescence.

Psychopharmacology (Berl) 2007 May 27;191(4):891-7. Epub 2007 Feb 27.

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

Introduction: Periadolescent nicotine exposure is associated with increased consumption and rewarding properties of abused drugs. In the case of peri- but not post-adolescent animals, these effects are persistent and last to adulthood, suggesting that early nicotine treatment may alter postnatal CNS development in ways that contribute to long-term problems with drug abuse.

Materials And Methods: To begin to identify brain regions that may be altered by developmental nicotine exposure, we have measured expression of a transcription factor, FosB, within a series of reward- and memory-related brain regions of Sprague-Dawley rats.

Results: FosB expression is known to acutely and cumulatively increase within a subset of brain regions, particularly nucleus accumbens, after exposure to many classes of abused drugs. Our results demonstrate that FosB is increased within nucleus accumbens and also the granule cell layer of hippocampal dentate gyrus after both peri- and post-adolescent nicotine exposure (0.4 mg kg(-1) day(-1) from days 34 to 43 and 60 to 69, respectively). In periadolescents, expression increases were detected 2 days after nicotine exposure, and persisted for weeks, through at least early adulthood at 80 days of age. In post-adolescents, expression increases persisted for at least 11 days to postnatal day 80.

Discussion: These findings demonstrate that nicotine treatment during both peri- and post-adolescence persistently alters activity of brain regions involved in reward and memory.

Conclusion: Because this altered gene expression occurs after both peri- and post-adolescent treatment, it cannot be directly responsible for increased consumption and rewarding properties of abused drugs previously established to be distinctly associated with periadolescent nicotine exposure.
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http://dx.doi.org/10.1007/s00213-007-0744-9DOI Listing
May 2007

Developmental pattern of CB1 cannabinoid receptor immunoreactivity in brain regions important to zebra finch (Taeniopygia guttata) song learning and control.

J Comp Neurol 2006 Jun;496(5):739-58

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

Zebra finches learn song during distinct developmental stages, making them an important species for studying mechanisms underlying vocal development. Distinct interconnected forebrain regions have been identified as important to specific features of zebra finch vocal learning and production. Because prior experiments have demonstrated that late postnatal exposure to cannabinoid agonists alters zebra finch song learning, we have sought to identify brain regions likely involved in it. By using an affinity-purified polyclonal antibody directed against the zebra finch CB(1) cannabinoid receptor, we have studied staining patterns in groups of males at 25, 50, 75, and >100 days of age (adults). A general waxing and waning of staining intensity were observed over this developmental period. Distinct staining of song-related brain regions was also noted. Early establishment of staining patterns within rostral telencephalic song regions [area X and lateral magnocellular nucleus of the anterior nidopallium (lMAN)] suggests a role in auditory learning. Later establishment and maintenance in adulthood of small somata and neuropil staining within regions of rostral telencephalon [HVC and robust nucleus of the arcopallium (RA)] are consistent with a vocal motor role for cannabinoid signaling. Our results provide insight into brain regions likely responsible for cannabinoid-altered vocal learning and add to accumulating evidence supporting an important role for cannabinoid signaling in CNS development.
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http://dx.doi.org/10.1002/cne.20963DOI Listing
June 2006

Periadolescent nicotine exposure causes heterologous sensitization to cocaine reinforcement.

Eur J Pharmacol 2005 Feb;509(2-3):161-4

Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27834 USA.

There is increasing concern that abuse of tobacco during periadolescence increases the potential for later abuse of other drugs. To test this hypothesis, Sprague-Dawley rats received once-daily injections of either water or 0.4 mg/kg nicotine from postnatal day 35 through 44. Beginning on postnatal day 80, animals were tested in a 12-day cocaine-induced conditioned place preference (CPP) paradigm. Prior nicotine treatment enhanced the dose-response to cocaine. CPP training with 3.0 mg/kg i.p. cocaine increased time in drug-paired chambers by 50% in control rats and 94% in nicotine-exposed animals. Thus, periadolescent nicotine exposure produced long-term sensitization to an indirect-acting dopamine agonist.
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http://dx.doi.org/10.1016/j.ejphar.2005.01.002DOI Listing
February 2005

Distinct periods of cannabinoid sensitivity during zebra finch vocal development.

Brain Res Dev Brain Res 2004 Nov;153(2):225-32

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

Zebra finch song is a form of vocal communication learned during at least two distinct stages of late postnatal development. During the first of these stages, termed auditory learning, nestlings memorize the song pattern of an adult male tutor, usually the father. During the second stage, sensory-motor learning, these song patterns are practiced and refined until a good copy is produced by adulthood. Vocal learning has made zebra finches a useful model for studying drug effects during vocal development. Prior work has shown that daily exposure to a modest dosage of the cannabinoid agonist WIN55212-2 (WIN) alters sensory-motor learning by reducing stereotypy scores and numbers of note types learned. Here we report that these two effects are produced independently during subperiods of the sensory-motor learning stage. Additional temporally distinct WIN effects during sensory-motor learning include differential incorporation of tutor-derived and improvised note types. We have also evaluated acute and chronic effects of WIN exposure on ability to encode a tutor's song during auditory learning, finding significant effects on stereotypy and distinct effects on note duration and internote intervals. Taken together, these results demonstrate the presence of distinct subperiods of cannabinoid sensitivity during zebra finch auditory and sensory-motor vocal development.
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http://dx.doi.org/10.1016/j.devbrainres.2004.09.002DOI Listing
November 2004

Endocannabinoids link feeding state and auditory perception-related gene expression.

J Neurosci 2004 Nov;24(44):10013-21

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA.

Singing by adult male zebra finches is a learned behavior important for courtship, kin recognition, and nest defense (Zann, 1996) and is inhibited by both brief periods of limited food availability and systemic injection of cannabinoids. These similar effects on singing, combined with increasing evidence for endocannabinoid involvement in feeding behavior, led us to evaluate a possible shared mechanism. We found that limited food availability both reduces singing in a cannabinoid antagonist-reversible manner and increases levels of the endocannabinoid 2-arachidonyl glycerol in various brain regions including the caudal telencephalon, an area that contains auditory telencephalon including the L2 subfield of L (L2) and caudal medial nidopallium (NCM). Development and use of an anti-zebra finch cannabinoid receptor type 1 (CB1) antibody demonstrates distinct, dense cannabinoid receptor expression within song regions including Area X, lMAN (lateral magnocellular nucleus of anterior nidopallium), HVC, RA (robust nucleus of arcopallium), and L2. NCM receives L2 projections and is implicated in integration of auditory information. Activity in this area, determined through expression of the transcription factor ZENK, is increased after exposure to unfamiliar song. Because previous work has shown that these novel song-stimulated increases in NCM activity are mitigated by cannabinoid exposure, we tested and found that similar effects on ZENK expression are produced by limiting food. Limited food-related reductions in the activity of NCM neurons were reversed by the cannabinoid antagonist SR141716A (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide), implicating CB1 cannabinoid receptor involvement. Taken together, these experiments indicate a link between feeding state and gene expression related to auditory perception that is mediated by endocannabinoid signaling.
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http://dx.doi.org/10.1523/JNEUROSCI.3298-04.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730237PMC
November 2004

Endocannabinoids link feeding state and auditory perception-related gene expression.

J Neurosci 2004 Nov;24(44):10013-21

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA.

Singing by adult male zebra finches is a learned behavior important for courtship, kin recognition, and nest defense (Zann, 1996) and is inhibited by both brief periods of limited food availability and systemic injection of cannabinoids. These similar effects on singing, combined with increasing evidence for endocannabinoid involvement in feeding behavior, led us to evaluate a possible shared mechanism. We found that limited food availability both reduces singing in a cannabinoid antagonist-reversible manner and increases levels of the endocannabinoid 2-arachidonyl glycerol in various brain regions including the caudal telencephalon, an area that contains auditory telencephalon including the L2 subfield of L (L2) and caudal medial nidopallium (NCM). Development and use of an anti-zebra finch cannabinoid receptor type 1 (CB1) antibody demonstrates distinct, dense cannabinoid receptor expression within song regions including Area X, lMAN (lateral magnocellular nucleus of anterior nidopallium), HVC, RA (robust nucleus of arcopallium), and L2. NCM receives L2 projections and is implicated in integration of auditory information. Activity in this area, determined through expression of the transcription factor ZENK, is increased after exposure to unfamiliar song. Because previous work has shown that these novel song-stimulated increases in NCM activity are mitigated by cannabinoid exposure, we tested and found that similar effects on ZENK expression are produced by limiting food. Limited food-related reductions in the activity of NCM neurons were reversed by the cannabinoid antagonist SR141716A (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide), implicating CB1 cannabinoid receptor involvement. Taken together, these experiments indicate a link between feeding state and gene expression related to auditory perception that is mediated by endocannabinoid signaling.
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http://dx.doi.org/10.1523/JNEUROSCI.3298-04.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730237PMC
November 2004

CB1 cannabinoid receptor activation inhibits a neural correlate of song recognition in an auditory/perceptual region of the zebra finch telencephalon.

J Neurobiol 2003 Sep;56(3):266-74

Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida 32306-1270, USA.

A notable consequence of CB1 cannabinoid receptor activation in vertebrates is an impairment of cognitive function related to learning and short-term memory. The mechanisms of this impairment remain unclear, but one possibility is that cannabinoids influence encoding of stimuli at sensory and/or perceptual levels. Here, by treating zebra finches with the cannabinoid agonist WIN55212-2 and then measuring expression of the transcription factor zenk following presentation of novel zebra finch song, we show that cannabinoid receptor activation differentially influences zenk expression in sensory versus perceptual regions of the songbird auditory telencephalon. That is, WIN55212-2 dose-dependently inhibited zenk expression in a region for auditory perception (NCM, the caudomedial neostriatum), but had no effect on zenk expression in the primary auditory area, the Field L complex. The inhibitory effects of WIN55212-2 on zenk expression in NCM were reversed by coadministration of the CB1-selective antagonist SR141716A. Moreover, we found that the habituation of the NCM zenk response to repeated presentation of the same song, a well-established neural correlate of song recognition, was blocked when birds were treated with WIN55212-2 during habituation trials. Our data suggest that activation of CB1 cannabinoid receptors can selectively influence perceptual and mnemonic aspects of auditory experience.
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http://dx.doi.org/10.1002/neu.10233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264579PMC
September 2003

Cannabinoid exposure alters learning of zebra finch vocal patterns.

Brain Res Dev Brain Res 2003 May;142(2):215-7

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

Using a well-established songbird model of juvenile vocal development, we have found that daily cannabinoid exposure at modest dosages alters sensory-motor vocal learning. Adult exposure did not change song that had already been learned. Our results demonstrate the potential for cannabinoid exposure to produce distinct effects during post-natal CNS development.
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http://dx.doi.org/10.1016/s0165-3806(03)00061-0DOI Listing
May 2003

Cannabinoid exposure alters learning of zebra finch vocal patterns.

Brain Res Dev Brain Res 2003 May;142(2):215-7

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

Using a well-established songbird model of juvenile vocal development, we have found that daily cannabinoid exposure at modest dosages alters sensory-motor vocal learning. Adult exposure did not change song that had already been learned. Our results demonstrate the potential for cannabinoid exposure to produce distinct effects during post-natal CNS development.
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http://dx.doi.org/10.1016/s0165-3806(03)00061-0DOI Listing
May 2003

Quantifying song bout production during zebra finch sensory-motor learning suggests a sensitive period for vocal practice.

Behav Brain Res 2002 Apr;131(1-2):57-65

Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, FL 32306-1270, USA.

Using an event-triggered recording system, the quantity of daily song bout production was measured weekly in male zebra finches (Taeniopygia guttata) during sensory-motor learning and at one year of age. Our aim was to ask whether the development of a stereotyped vocal pattern involves a practice-driven component. If so, we hypothesized that juvenile males learning song should sing more often than adults reciting a vocal pattern they had already learned, and that greater levels of juvenile singing should be associated with improvement in the quality of the adult song. Across the period measured (36-365 days of age), subjects showed an inverted U-shaped pattern of daily song bout production. Song bout production was lowest during subsong, with increased production associated with plastic song and song crystallization, although individual differences were large. Daily song bout production decreased in adulthood. Higher levels of song bout production during plastic song correlated with fewer sequencing errors in adult song patterns (r(2)=0.77). In contrast, quantity of singing during song crystallization showed no relationship to vocal stereotypy (r(2)=0.002). Our data suggest a sensitive period for vocal practice during zebra finch sensory-motor learning with consequences for the note-sequence fidelity of the adult vocal pattern.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264566PMC
http://dx.doi.org/10.1016/s0166-4328(01)00374-6DOI Listing
April 2002
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