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Miranda J.A.,Emory University | Miranda J.A.,Center for Behavioral Neuroscience | Shepard K.N.,Emory University | Shepard K.N.,Center for Behavioral Neuroscience | And 4 more authors.
PLoS ONE | Year: 2014

Subcortical auditory nuclei were traditionally viewed as non-plastic in adulthood so that acoustic information could be stably conveyed to higher auditory areas. Studies in a variety of species, including humans, now suggest that prolonged acoustic training can drive long-lasting brainstem plasticity. The neurobiological mechanisms for such changes are not well understood in natural behavioral contexts due to a relative dearth of in vivo animal models in which to study this. Here, we demonstrate in a mouse model that a natural life experience with increased demands on the auditory system - motherhood - is associated with improved temporal processing in the subcortical auditory pathway. We measured the auditory brainstem response to test whether mothers and pup-naïve virgin mice differed in temporal responses to both broadband and tone stimuli, including ultrasonic frequencies found in mouse pup vocalizations. Mothers had shorter latencies for early ABR peaks, indicating plasticity in the auditory nerve and the cochlear nucleus. Shorter interpeak latency between waves IV and V also suggest plasticity in the inferior colliculus. Hormone manipulations revealed that these cannot be explained solely by estrogen levels experienced during pregnancy and parturition in mothers. In contrast, we found that pup-care experience, independent of pregnancy and parturition, contributes to shortening auditory brainstem response latencies. These results suggest that acoustic experience in the maternal context imparts plasticity on early auditory processing that lasts beyond pup weaning. In addition to establishing an animal model for exploring adult auditory brainstem plasticity in a neuroethological context, our results have broader implications for models of perceptual, behavioral and neural changes that arise during maternity, where subcortical sensorineural plasticity has not previously been considered. © 2014 Miranda et al.


Latzman R.D.,Georgia State University | Young L.J.,Center for Translational Social Neuroscience | Young L.J.,Emory University | Hopkins W.D.,Georgia State University | Hopkins W.D.,Yerkes National Primate Research Center
Psychophysiology | Year: 2016

The current study aimed to systematically investigate genetic and neuroanatomical correlates of individual variation in scratching behaviors, a well-validated animal-behavioral indicator of negative emotional states with clear links to the NIMH Research Domain Criteria (RDoC) response to potential harm ("anxiety") construct within the Negative Valence Systems domain. Utilizing data from a sample of 76 captive chimpanzees (Pan troglodytes), we (a) examined the association between scratching and presence or absence of the RS3-containing DupB element in the AVPR1A 5' flanking region, (b) utilized voxel-based morphometry (VBM) to identify gray matter (GM) voxel clusters that differentiated AVPR1A genotype, and (c) conducted a VBM-guided voxel-of-interest analysis to examine the association between GM intensity and scratching. AVPR1A evidenced sexually dimorphic associations with scratching. VBM analyses revealed significant differences in GM by genotype across twelve clusters largely in the frontal cortex. Regions differentiating AVPR1A genotype showed sex-specific associations with scratching. Results suggest that sexually dimorphic associations between AVPR1A and scratching may be explained by genotype-specific neuroanatomical variation. The current study provides an example of the way in which chimpanzee research is uniquely poised for multilevel, systematic investigations of psychopathology-relevant constructs within the context of the RDoC framework. © 2016 Society for Psychophysiological Research.


PubMed | Center for Translational Social Neuroscience and Georgia State University
Type: Journal Article | Journal: Psychophysiology | Year: 2016

The current study aimed to systematically investigate genetic and neuroanatomical correlates of individual variation in scratching behaviors, a well-validated animal-behavioral indicator of negative emotional states with clear links to the NIMH Research Domain Criteria (RDoC) response to potential harm (anxiety) construct within the Negative Valence Systems domain. Utilizing data from a sample of 76 captive chimpanzees (Pan troglodytes), we (a) examined the association between scratching and presence or absence of the RS3-containing DupB element in the AVPR1A 5 flanking region, (b) utilized voxel-based morphometry (VBM) to identify gray matter (GM) voxel clusters that differentiated AVPR1A genotype, and (c) conducted a VBM-guided voxel-of-interest analysis to examine the association between GM intensity and scratching. AVPR1A evidenced sexually dimorphic associations with scratching. VBM analyses revealed significant differences in GM by genotype across twelve clusters largely in the frontal cortex. Regions differentiating AVPR1A genotype showed sex-specific associations with scratching. Results suggest that sexually dimorphic associations between AVPR1A and scratching may be explained by genotype-specific neuroanatomical variation. The current study provides an example of the way in which chimpanzee research is uniquely poised for multilevel, systematic investigations of psychopathology-relevant constructs within the context of the RDoC framework.


Bruner E.,National Research Center sobre la Evolucion Humana | Preuss T.M.,Emory University | Preuss T.M.,Center for Translational Social Neuroscience | Chen X.,Emory University | And 2 more authors.
Brain Structure and Function | Year: 2016

The evolution of neurocranial morphology in Homo sapiens is characterized by bulging of the parietal region, a feature unique to our species. In modern humans, expansion of the parietal surface occurs during the first year of life, in a morphogenetic stage which is absent in chimpanzees and Neandertals. A similar variation in brain shape among living adult humans is associated with expansion of the precuneus. Using MRI-derived structural brain templates, we compare medial brain morphology between humans and chimpanzees through shape analysis and geometrical modeling. We find that the main spatial difference is a prominent expansion of the precuneus in our species, providing further evidence of evolutionary changes associated with this area. The precuneus is a major hub of brain organization, a central node of the default-mode network, and plays an essential role in visuospatial integration. Together, the comparative neuroanatomical and paleontological evidence suggest that precuneus expansion is a neurological specialization of H. sapiens that evolved in the last 150,000 years that may be associated with recent human cognitive specializations. © 2016 Springer-Verlag Berlin Heidelberg


PubMed | Center for Translational Social Neuroscience, National Research Center sobre la Evolucion Humana and Emory University
Type: | Journal: Brain structure & function | Year: 2016

The evolution of neurocranial morphology in Homo sapiens is characterized by bulging of the parietal region, a feature unique to our species. In modern humans, expansion of the parietal surface occurs during the first year of life, in a morphogenetic stage which is absent in chimpanzees and Neandertals. A similar variation in brain shape among living adult humans is associated with expansion of the precuneus. Using MRI-derived structural brain templates, we compare medial brain morphology between humans and chimpanzees through shape analysis and geometrical modeling. We find that the main spatial difference is a prominent expansion of the precuneus in our species, providing further evidence of evolutionary changes associated with this area. The precuneus is a major hub of brain organization, a central node of the default-mode network, and plays an essential role in visuospatial integration. Together, the comparative neuroanatomical and paleontological evidence suggest that precuneus expansion is a neurological specialization of H. sapiens that evolved in the last 150,000years that may be associated with recent human cognitive specializations.


Smith A.L.,Emory University | Smith A.L.,Center for Translational Social Neuroscience | Freeman S.M.,Center for Translational Social Neuroscience | Stehouwer J.S.,Emory University | And 4 more authors.
Bioorganic and Medicinal Chemistry | Year: 2012

Compounds 1-4 were synthesized and investigated for selectivity and potency for the oxytocin receptor (OTR) to determine their viability as radioactive ligands. Binding assays determined 1-4 to have high binding affinity for both the human and rodent OTR and also have high selectivity for the human OTR over human vasopressin V1a receptors (V1aR). Inadequate selectivity for OTR over V1aR was found for rodent receptors in all four compounds. The radioactive (C-11, F-18, and I-125) derivatives of 1-4 were synthesized and investigated for use as autoradiography and positron emission tomography (PET) ligands. Receptor autoradiography performed with [ 125I]1 and [ 125I]2 on rodent brain slices provided the first small molecule radioligand images of the OTR and V1aR. Biodistribution studies determined [ 125I]1 and [ 125I]2 were adequate for in vivo peripheral investigations, but not for central investigations due to low uptake within the brain. A biodistribution study with [ 18F]3 suggested brain uptake occurred slowly over time. PET imaging studies with [ 18F]3 and [ 11C]4 using a rat model provided insufficient uptake in the brain over a 90 and 45 min scan times respectively to merit further investigations in non-human primates. © 2012 Published by Elsevier Ltd. All rights reserved.


Barrett C.E.,Center for Translational Social Neuroscience | Barrett C.E.,Yerkes National Primate Research Center | Keebaugh A.C.,Center for Translational Social Neuroscience | Keebaugh A.C.,Yerkes National Primate Research Center | And 8 more authors.
Hormones and Behavior | Year: 2013

Polymorphisms in noncoding regions of the vasopressin 1a receptor gene (Avpr1a) are associated with a variety of socioemotional characteristics in humans, chimpanzees, and voles, and may impact behavior through a site-specific variation in gene expression. The socially monogamous prairie vole offers a unique opportunity to study such neurobiological control of individual differences in complex behavior. Vasopressin 1a receptor (V1aR) signaling is necessary for the formation of the pair bond in males, and prairie voles exhibit greater V1aR binding in the reward-processing ventral pallidum than do asocial voles of the same genus. Diversity in social behavior within prairie voles has been correlated to natural variation in neuropeptide receptor expression in specific brain regions. Here we use RNA interference to examine the causal relationship between intraspecific variation in V1aR and behavioral outcomes, by approximating the degree of naturalistic variation in V1aR expression. Juvenile male prairie voles were injected with viral vectors expressing shRNA sequences targeting Avpr1a mRNA into the ventral pallidum. Down-regulation of pallidal V1aR density resulted in a significant impairment in the preference for a mated female partner and a reduction in anxiety-like behavior in adulthood. No effect on alloparenting was detected. These data demonstrate that within-species naturalistic-like variation in V1aR expression has a profound effect on individual differences in social attachment and emotionality. RNA interference may prove to be a useful technique to unite the fields of behavioral ecology and neurogenetics to perform ethologically relevant studies of the control of individual variation and offer insight into the evolutionary mechanisms leading to behavioral diversity. © 2013 Elsevier Inc.


Smith A.L.,Center for Translational Social Neuroscience | Smith A.L.,Emory University | Freeman S.M.,Center for Translational Social Neuroscience | Voll R.J.,Emory University | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

Compound L-368,899 was successfully alkylated with [11C] iodomethane to generate the oxytocin receptor selective (2R)-2-amino-N-((2S)-7, 7-dimethyl-1-(((4-(o-tolyl)piperazin-1-yl)sulfonyl)methyl)bicyclo[2.2.1] heptan-2-yl)-N-[11C]methyl-3-(methylsulfonyl)propanamide ([ 11C]1) with very high radiochemical purity and high specific activity. PET imaging studies were performed with [11C]1 to investigate brain penetration and oxytocin receptor uptake using rat and cynomolgus monkey models. For rat baseline scans, brain penetration was observed with [11C]1, but no specific uptake could be distinguished in the brain region. By administering a peptide oxytocin receptor selective antagonist for peripheral blocking of oxytocin receptors, the uptake of [11C]1 was amplified in the rat brain temporarily to enable some visual uptake within the rat brain. A baseline scan of [11C]1 in a cynomolgus monkey model resulted in no detectable specific uptake in anticipated regions, but activity did accumulate in the choroid plexus. © 2012 Elsevier Ltd. All rights reserved.


Numan M.,Rio Rancho | Young L.J.,Center for Translational Social Neuroscience
Hormones and Behavior | Year: 2016

This article is part of a Special Issue "Parental Care". Mother-infant bonding is a characteristic of virtually all mammals. The maternal neural system may have provided the scaffold upon which other types of social bonds in mammals have been built. For example, most mammals exhibit a polygamous mating system, but monogamy and pair bonding between mating partners occur in ~ 5% of mammalian species. In mammals, it is plausible that the neural mechanisms that promote mother-infant bonding have been modified by natural selection to establish the capacity to develop a selective bond with a mate during the evolution of monogamous mating strategies. Here we compare the details of the neural mechanisms that promote mother-infant bonding in rats and other mammals with those that underpin pair bond formation in the monogamous prairie vole. Although details remain to be resolved, remarkable similarities and a few differences between the mechanisms underlying these two types of bond formation are revealed. For example, amygdala and nucleus accumbens-ventral pallidum (NA-VP) circuits are involved in both types of bond formation, and dopamine and oxytocin actions within NA appear to promote the synaptic plasticity that allows either infant or mating partner stimuli to persistently activate NA-VP attraction circuits, leading to an enduring social attraction and bonding. Further, although the medial preoptic area is essential for maternal behavior, its role in pair bonding remains to be determined. Our review concludes by examining the broader implications of this comparative analysis, and evidence is provided that the maternal care system may have also provided the basic neural foundation for other types of strong social relationships, beyond pair bonding, in mammals, including humans. © 2015 Elsevier Inc.


Smith A.L.,Emory University | Smith A.L.,Center for Translational Social Neuroscience | Freeman S.M.,Center for Translational Social Neuroscience | Voll R.J.,Emory University | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

The compound 1-(1-(2-(2-(2-fluoroethoxy)-4-(piperidin-4-yloxy)phenyl) acetyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (1) was synthesized and positively evaluated in vitro for high potency and selectivity with human oxytocin receptors. The positron emitting analogue, [F-18]1, was synthesized and investigated in vivo via PET imaging using rat and cynomolgus monkey models. PET imaging studies in female Sprague-Dawley rats suggested [F-18]1 reached the brain and accumulated in various regions of the brain, but washed out too rapidly for adequate quantification and localization. In vivo PET imaging studies in a male cynomolgus monkey suggested [F-18]1 had limited brain penetration while specific uptake of radioactivity significantly accumulated within the vasculature of the cerebral ventricles in areas representative of the choroid plexus. © 2013 Elsevier Ltd. All rights reserved.

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