RESUMEN
Adult pair bonding involves dramatic changes in the perception and valuation of another individual. One key change is that partners come to reliably activate the brain's reward system, although the precise neural mechanisms by which partners become rewarding during sociosexual interactions leading to a bond remain unclear. Here we show, using a prairie vole (Microtus ochrogaster) model of social bonding, how a functional circuit from the medial prefrontal cortex to nucleus accumbens is dynamically modulated to enhance females' affiliative behaviour towards a partner. Individual variation in the strength of this functional connectivity, particularly after the first mating encounter, predicts how quickly animals begin affiliative huddling with their partner. Rhythmically activating this circuit in a social context without mating biases later preference towards a partner, indicating that this circuit's activity is not just correlated with how quickly animals become affiliative but causally accelerates it. These results provide the first dynamic view of corticostriatal activity during bond formation, revealing how social interactions can recruit brain reward systems to drive changes in affiliative behaviour.
Asunto(s)
Arvicolinae/fisiología , Arvicolinae/psicología , Núcleo Accumbens/fisiología , Apareamiento , Corteza Prefrontal/fisiología , Recompensa , Conducta Social , Animales , Femenino , Masculino , Preferencia en el Apareamiento Animal/fisiología , Núcleo Accumbens/citología , Corteza Prefrontal/citología , Factores de TiempoRESUMEN
Many behaviors are associated with heritable genetic variation [Kendler and Greenspan (2006) Am J Psychiatry 163:1683-1694]. Genetic mapping has revealed genomic regions or, in a few cases, specific genes explaining part of this variation [Bendesky and Bargmann (2011) Nat Rev Gen 12:809-820]. However, the genetic basis of behavioral evolution remains unclear. Here we investigate the evolution of an innate extended phenotype, bower building, among cichlid fishes of Lake Malawi. Males build bowers of two types, pits or castles, to attract females for mating. We performed comparative genome-wide analyses of 20 bower-building species and found that these phenotypes have evolved multiple times with thousands of genetic variants strongly associated with this behavior, suggesting a polygenic architecture. Remarkably, F1 hybrids of a pit-digging and a castle-building species perform sequential construction of first a pit and then a castle bower. Analysis of brain gene expression in these hybrids showed that genes near behavior-associated variants display behavior-dependent allele-specific expression with preferential expression of the pit-digging species allele during pit digging and of the castle-building species allele during castle building. These genes are highly enriched for functions related to neurodevelopment and neural plasticity. Our results suggest that natural behaviors are associated with complex genetic architectures that alter behavior via cis-regulatory differences whose effects on gene expression are specific to the behavior itself.
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Conducta Animal/fisiología , Cíclidos/genética , Animales , Mapeo Cromosómico , Expresión Génica , Regulación de la Expresión Génica/genética , Variación Genética/genética , Genoma/genética , Estudio de Asociación del Genoma Completo , Lagos , Malaui , MasculinoRESUMEN
Social behavior is regulated by conserved neural networks across vertebrates. Variation in the organization of neuropeptide systems across these networks is thought to contribute to individual and species diversity in network function during social contexts. For example, oxytocin (OT) is an ancient neuropeptide that binds to OT receptors (OTRs) in the brain and modulates social and reproductive behavior across vertebrate species, including humans. Central OTRs exhibit extraordinarily diverse expression patterns that are associated with individual and species differences in social behavior. In voles, OTR density in the nucleus accumbens (NAc)-a region important for social and reward learning-is associated with individual and species variation in social attachment behavior. Here we test whether OTRs in the NAc modulate a social salience network (SSN)-a network of interconnected brain nuclei thought to encode valence and incentive salience of sociosensory cues-during a social context in the socially monogamous male prairie vole. Using a selective OTR antagonist, we test whether activation of OTRs in the NAc during sociosexual interaction and mating modulates expression of the immediate early gene product Fos across nuclei of the SSN. We show that blockade of endogenous OTR signaling in the NAc during sociosexual interaction and mating does not strongly modulate levels of Fos expression in individual nodes of the network, but strongly modulates patterns of correlated Fos expression between the NAc and other SSN nuclei.
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Arvicolinae/fisiología , Red Nerviosa/fisiología , Receptores de Oxitocina/fisiología , Conducta Social , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Femenino , Masculino , Red Nerviosa/efectos de los fármacos , Red Nerviosa/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Oxitocina/farmacología , Oxitocina/fisiología , Apareamiento , Receptores de Oxitocina/metabolismo , Reproducción/efectos de los fármacos , Reproducción/fisiología , Conducta Sexual Animal/efectos de los fármacosRESUMEN
Oxytocin (OT) is a deeply conserved nonapeptide that acts both peripherally and centrally to modulate reproductive physiology and sociosexual behavior across divergent taxa, including humans. In vertebrates, the distribution of the oxytocin receptor (OTR) in the brain is variable within and across species, and OTR signaling is critical for a variety of species-typical social and reproductive behaviors, including affiliative and pair bonding behaviors in multiple socially monogamous lineages of fishes, birds, and mammals. Early work in prairie voles suggested that the endogenous OT system modulates mating-induced partner preference formation in females but not males; however, there is significant evidence that central OTRs may modulate pair bonding behavior in both sexes. In addition, it remains unclear how transient windows of central OTR signaling during sociosexual interaction modulate neural activity to produce enduring shifts in sociobehavioral phenotypes, including the formation of selective social bonds. Here we re-examine the role of the central OT system in partner preference formation in male prairie voles using a selective OTR antagonist delivered intracranially. We then use the same antagonist to examine how central OTRs modulate behavior and immediate early gene (Fos) expression, a metric of neuronal activation, in males during brief sociosexual interaction with a female. Our results suggest that, as in females, OTR signaling is critical for partner preference formation in males and enhances correlated activation across sensory and reward processing brain areas during sociosexual interaction. These results are consistent with the hypothesis that central OTR signaling facilitates social bond formation by coordinating activity across a pair bonding neural network.
Asunto(s)
Arvicolinae/fisiología , Preferencia en el Apareamiento Animal , Apareamiento , Prosencéfalo/metabolismo , Receptores de Oxitocina/fisiología , Animales , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Femenino , Humanos , Infusiones Intraventriculares , Masculino , Red Nerviosa/efectos de los fármacos , Red Nerviosa/metabolismo , Oxitocina/administración & dosificación , Prosencéfalo/efectos de los fármacos , Receptores de Oxitocina/metabolismoRESUMEN
The telencephalon has undergone remarkable diversification and expansion throughout vertebrate evolution, exhibiting striking variations in structural and functional complexity. Nevertheless, fundamental features are shared across vertebrate taxa, such as the presence of distinct regions including the pallium, subpallium, and olfactory structures. Teleost fishes have a uniquely "everted" telencephalon, which has confounded comparisons of their brain regions to other vertebrates. Here we combine spatial transcriptomics and single nucleus RNA-sequencing to generate a spatially-resolved transcriptional atlas of the Mchenga conophorus cichlid fish telencephalon. We then compare cell-types and anatomical regions in the cichlid telencephalon with those in amphibians, reptiles, birds, and mammals. We uncover striking transcriptional similarities between cell-types in the fish telencephalon and subpallial, hippocampal, and cortical cell-types in tetrapods, and find support for partial eversion of the teleost telencephalon. Ultimately, our work lends new insights into the organization and evolution of conserved cell-types and regions in the vertebrate forebrain.
Asunto(s)
Cíclidos , Prosencéfalo , Telencéfalo , Animales , Telencéfalo/citología , Prosencéfalo/citología , Cíclidos/genética , Transcriptoma , Vertebrados/genética , Evolución BiológicaRESUMEN
BACKGROUND: Sexual differentiation of the brain occurs in all major vertebrate lineages but is not well understood at a molecular and cellular level. Unlike most vertebrates, sex-changing fishes have the remarkable ability to change reproductive sex during adulthood in response to social stimuli, offering a unique opportunity to understand mechanisms by which the nervous system can initiate and coordinate sexual differentiation. METHODS: This study explores sexual differentiation of the forebrain using single nucleus RNA-sequencing in the anemonefish Amphiprion ocellaris, producing the first cellular atlas of a sex-changing brain. RESULTS: We uncover extensive sex differences in cell type-specific gene expression, relative proportions of cells, baseline neuronal excitation, and predicted inter-neuronal communication. Additionally, we identify the cholecystokinin, galanin, and estrogen systems as central molecular axes of sexual differentiation. Supported by these findings, we propose a model of sexual differentiation in the conserved vertebrate social decision-making network spanning multiple subtypes of neurons and glia, including neuronal subpopulations within the preoptic area that are positioned to regulate gonadal differentiation. CONCLUSIONS: This work deepens our understanding of sexual differentiation in the vertebrate brain and defines a rich suite of molecular and cellular pathways that differentiate during adult sex change in anemonefish.
This study provides key insights into brain sex differences in sex-changing anemonefish (Amphiprion ocellaris), a species that changes sex in adulthood in response to the social environment. Using single nucleus RNA-sequencing, the study provides the first brain cellular atlas showing sex differences in two crucial reproductive areas: the preoptic area and telencephalon. The research identifies notable sex-differences in cell-type proportions and gene expression, particularly in radial glia and glutamatergic neurons that co-express the neuropeptide cholecystokinin. It also highlights differences in preoptic area neurons likely involved in gonadal regulation. This work deepens our understanding of sexual differentiation of the brain in vertebrates, especially those capable of adult sex change, and illuminates key molecular and cellular beginning and endpoints of the process.
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Prosencéfalo , Caracteres Sexuales , Diferenciación Sexual , Animales , Prosencéfalo/fisiología , Prosencéfalo/metabolismo , Masculino , Femenino , Diferenciación Sexual/fisiología , Neuronas/fisiología , Neuronas/metabolismo , Peces/fisiología , Perciformes/fisiología , Galanina/metabolismo , Galanina/genética , Colecistoquinina/metabolismoRESUMEN
Sexual differentiation of the brain occurs in all major vertebrate lineages but is not well understood at a molecular and cellular level. Unlike most vertebrates, sex-changing fishes have the remarkable ability to change reproductive sex during adulthood in response to social stimuli, offering a unique opportunity to understand mechanisms by which the nervous system can initiate and coordinate sexual differentiation. This study explores sexual differentiation of the forebrain using single nucleus RNA-sequencing in the anemonefish Amphiprion ocellaris, producing the first cellular atlas of a sex-changing brain. We uncover extensive sex differences in cell type-specific gene expression, relative proportions of cells, baseline neuronal excitation, and predicted inter-neuronal communication. Additionally, we identify the cholecystokinin, galanin, and estrogen systems as central molecular axes of sexual differentiation. Supported by these findings, we propose a model of neurosexual differentiation in the conserved vertebrate social decision-making network spanning multiple subtypes of neurons and glia, including neuronal subpopulations within the preoptic area that are positioned to regulate gonadal differentiation. This work deepens our understanding of sexual differentiation in the vertebrate brain and defines a rich suite of molecular and cellular pathways that differentiate during adult sex change in anemonefish.
RESUMEN
The telencephalon has undergone remarkable diversification and expansion throughout vertebrate evolution, exhibiting striking differences in structural and functional complexity. Nevertheless, fundamental features are shared across vertebrate taxa, such as the presence of distinct regions including the pallium, subpallium, and olfactory structures. Teleost fishes have a uniquely 'everted' telencephalon, which has made it challenging to compare brain regions in fish to those in other vertebrates. Here we combine spatial transcriptomics and single-nucleus RNA-sequencing to generate a spatially-resolved transcriptional atlas of the cichlid fish telencephalon. We then compare cell-types and anatomical regions in the cichlid telencephalon with those in amphibians, reptiles, birds, and mammals. We uncover striking transcriptional similarities between cell populations in the fish telencephalon and subpallial, hippocampal, and cortical cell populations in tetrapods. Ultimately, our work lends new insights into the organization and evolution of conserved cell-types and regions in the vertebrate forebrain.
RESUMEN
Social behaviors are diverse in nature, but it is unclear how conserved genes, brain regions, and cell populations generate this diversity. Here we investigate bower-building, a recently-evolved social behavior in cichlid fishes. We use single nucleus RNA-sequencing in 38 individuals to show signatures of recent behavior in specific neuronal populations, and building-associated rebalancing of neuronal proportions in the putative homolog of the hippocampal formation. Using comparative genomics across 27 species, we trace bower-associated genome evolution to a subpopulation of glia lining the dorsal telencephalon. We show evidence that building-associated neural activity and a departure from quiescence in this glial subpopulation together regulate hippocampal-like neuronal rebalancing. Our work links behavior-associated genomic variation to specific brain cell types and their functions, and suggests a social behavior has evolved through changes in glia.
Asunto(s)
Cíclidos , Animales , Cíclidos/genética , Conducta Social , Genoma , Genómica , Secuencia de BasesRESUMEN
Oxytocin (OXT) is a highly conserved neuropeptide that modulates social cognition, and variation in its receptor gene (Oxtr) is associated with divergent social phenotypes. The cellular mechanisms connecting Oxtr genotype to social phenotype remain obscure. We exploit an association between Oxtr polymorphisms and striatal-specific OXTR density in prairie voles to investigate how OXTR signaling influences the brain transcriptome. We discover widespread, OXTR signaling-dependent transcriptomic changes. Interestingly, OXTR signaling robustly modulates gene expression of C-type lectin-like receptors (CTLRs) in the natural killer gene complex, a genomic region associated with immune function. CTLRs are positioned to control microglial synaptic pruning; a process important for shaping neural circuits. Similar relationships between OXTR RNA and CTLR gene expression were found in human striatum. These data suggest a potential molecular mechanism by which variation in OXTR signaling due to genetic background and/or life-long social experiences, including nurturing/neglect, may affect circuit connectivity and social behavior.
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Lake Malawi cichlid fishes exhibit extensive divergence in form and function built from a relatively small number of genetic changes. We compared the genomes of rock- and sand-dwelling species and asked which genetic variants differed among the groups. We found that 96% of differentiated variants reside in non-coding sequence but these non-coding diverged variants are evolutionarily conserved. Genome regions near differentiated variants are enriched for craniofacial, neural and behavioral categories. Following leads from genome sequence, we used rock- vs. sand-species and their hybrids to (i) delineate the push-pull roles of BMP signaling and irx1b in the specification of forebrain territories during gastrulation and (ii) reveal striking context-dependent brain gene expression during adult social behavior. Our results demonstrate how divergent genome sequences can predict differences in key evolutionary traits. We highlight the promise of evolutionary reverse genetics-the inference of phenotypic divergence from unbiased genome sequencing and then empirical validation in natural populations.
Asunto(s)
Conducta Animal , Evolución Biológica , Encéfalo/fisiología , Genoma , Genómica , Animales , Cíclidos/clasificación , Cíclidos/fisiología , Genómica/métodos , Filogenia , TranscriptomaRESUMEN
Many behaviors that are critical for survival and reproduction are expressed over extended time periods. The ability to inexpensively record and store large volumes of video data creates new opportunities to understand the biological basis of these behaviors and simultaneously creates a need for tools that can automatically quantify behaviors from large video datasets. Here, we demonstrate that 3D Residual Networks can be used to classify an array of complex behaviors in Lake Malawi cichlid fishes. We first apply pixel-based hidden Markov modeling combined with density-based spatiotemporal clustering to identify sand disturbance events. After this, a 3D ResNet, trained on 11,000 manually annotated video clips, accurately (>76%) classifies the sand disturbance events into 10 fish behavior categories, distinguishing between spitting, scooping, fin swipes, and spawning. Furthermore, animal intent can be determined from these clips, as spits and scoops performed during bower construction are classified independently from those during feeding.
RESUMEN
In the wild, behaviors are often expressed over long time periods in complex and dynamic environments, and many behaviors include direct interaction with the environment itself. However, measuring behavior in naturalistic settings is difficult, and this has limited progress in understanding the mechanisms underlying many naturally evolved behaviors that are critical for survival and reproduction. Here we describe an automated system for measuring long-term bower construction behaviors in Lake Malawi cichlid fishes, in which males use their mouths to sculpt sand into large species-specific structures for courtship and mating. We integrate two orthogonal methods, depth sensing and action recognition, to simultaneously track the developing bower structure and the thousands of individual sand manipulation behaviors performed throughout construction. By registering these two data streams, we show that behaviors can be topographically mapped onto a dynamic 3D sand surface through time. The system runs reliably in multiple species, across many aquariums simultaneously, and for up to weeks at a time. Using this system, we show strong differences in construction behavior and bower form that reflect species differences in nature, and we gain new insights into spatial, temporal, social dimensions of bower construction, feeding, and quivering behaviors. Taken together, our work highlights how low-cost tools can automatically quantify behavior in naturalistic and social environments over long timescales in the lab.
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Cíclidos/metabolismo , Recolección de Datos/métodos , Animales , Conducta Animal/clasificación , Conducta Animal/fisiología , Procesamiento de Imagen Asistido por Computador/métodos , Lagos , Malaui , Masculino , Reconocimiento de Normas Patrones Automatizadas/métodos , Reproducción/fisiología , Conducta Sexual Animal/fisiologíaRESUMEN
Neural circuits implicated in drug conditioning, craving and relapse overlap extensively with those involved in natural reward and reinforcement. To determine whether specificity could be detected in conditioned brain responses to drugs versus food, male outbred HSD:ICR mice were conditioned to a common environment using either 20 mg/kg cocaine (ip) or a familiar food (under food restriction). The mice were then re-exposed to the same environment without the reinforcer and patterns of brain activation were compared using immunohistochemical detection of Fos. Conditioned place preference tests were conducted first to establish relative potency of each reward and facilitate analysis of correlations between Fos and motivation. Place preference was stronger for cocaine than food. Food- but not cocaine-paired cues increased Fos in the paraventricular hypothalamic nucleus whereas the opposite occurred for prefrontal, cingulate and piriform cortices. Individual differences in cocaine place preference were negatively correlated with Fos in the prefrontal cortex. One difference between drugs and natural reinforcers may be lack of feedback from the periphery for drugs which may circumvent control from the hypothalamus in the development of reinforcement circuits.
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Encéfalo/anatomía & histología , Cocaína/administración & dosificación , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/administración & dosificación , Privación de Alimentos/fisiología , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Mapeo Encefálico , Recuento de Células , Condicionamiento Operante/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Masculino , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Neuroanatomía/métodos , Proteínas Oncogénicas v-fos/metabolismoRESUMEN
The tremendous diversity of animal behaviors has inspired generations of scientists from an array of biological disciplines. To complement investigations of ecological and evolutionary factors contributing to behavioral evolution, modern sequencing, gene editing, computational and neuroscience tools now provide a means to discover the proximate mechanisms upon which natural selection acts to generate behavioral diversity. Social behaviors are motivated behaviors that can differ tremendously between closely related species, suggesting phylogenetic plasticity in their underlying biological mechanisms. In addition, convergent evolution has repeatedly given rise to similar forms of social behavior and mating systems in distantly related species. Social behavioral divergence and convergence provides an entry point for understanding the neurogenetic mechanisms contributing to behavioral diversity. We argue that the greatest strides in discovering mechanisms contributing to social behavioral diversity will be achieved through integration of interdisciplinary comparative approaches with modern tools in diverse species systems. We review recent advances and future potential for discovering mechanisms underlying social behavioral variation; highlighting patterns of social behavioral evolution, oxytocin and vasopressin neuropeptide systems, genetic/transcriptional "toolkits," modern experimental tools, and alternative species systems, with particular emphasis on Microtine rodents and Lake Malawi cichlid fishes.
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Conducta Animal/fisiología , Evolución Biológica , Animales , Neurociencia Cognitiva , Simulación por Computador , Genómica , Conducta SocialRESUMEN
Oxytocin- and vasopressin-related systems are present in invertebrate and vertebrate bilaterian animals, including humans, and exhibit conserved neuroanatomical and functional properties. In vertebrates, these systems innervate conserved neural networks that regulate social learning and behavior, including conspecific recognition, social attachment, and parental behavior. Individual and species-level variation in central organization of oxytocin and vasopressin systems has been linked to individual and species variation in social learning and behavior. In humans, genetic polymorphisms in the genes encoding oxytocin and vasopressin peptides and/or their respective target receptors have been associated with individual variation in social recognition, social attachment phenotypes, parental behavior, and psychiatric phenotypes such as autism. Here we describe both conserved and variable features of central oxytocin and vasopressin systems in the context of social behavioral diversity, with a particular focus on neural networks that modulate social learning, behavior, and salience of sociosensory stimuli during species-typical social contexts.
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Red Nerviosa , Conducta Social , Animales , Trastorno Autístico , Humanos , Oxitocina , VasopresinasRESUMEN
Loss of a partner can have severe effects on mental health. Here we explore the neural mechanisms underlying increased passive stress-coping, indicative of depressive-like behavior, following the loss of the female partner in the monogamous male prairie vole. We demonstrate that corticotropin-releasing factor receptor 2 (CRFR2) in the nucleus accumbens shell mediates social loss-induced passive coping. Further, we show that partner loss compromises the oxytocin system through multiple mechanisms. Finally, we provide evidence for an interaction of the CRFR2 and oxytocin systems in mediating the emotional consequences of partner loss. Our results suggest that chronic activation of CRFR2 and suppression of striatal oxytocin signaling following partner loss result in an aversive emotional state that may share underlying mechanisms with bereavement. We propose that the suppression of oxytocin signaling is likely adaptive during short separations to encourage reunion with the partner and may have evolved to maintain long-term partnerships. Additionally, therapeutic strategies targeting these systems should be considered for treatment of social loss-mediated depression.
Asunto(s)
Adaptación Psicológica , Arvicolinae/fisiología , Muerte , Núcleo Accumbens/fisiología , Oxitocina/fisiología , Apareamiento , Receptores de Hormona Liberadora de Corticotropina/fisiología , Animales , Autorradiografía , Proteínas Bacterianas , Cuerpo Estriado/fisiología , Hormona Liberadora de Corticotropina/administración & dosificación , Hormona Liberadora de Corticotropina/farmacología , Femenino , Infusiones Intraventriculares , Proteínas Luminiscentes , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Microinyecciones , Neuronas/fisiología , Núcleo Accumbens/efectos de los fármacos , Oxitocina/administración & dosificación , Oxitocina/farmacología , Núcleo Hipotalámico Paraventricular/fisiología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/farmacología , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/farmacología , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/farmacología , Radioinmunoensayo , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Receptores de Oxitocina/antagonistas & inhibidores , Receptores de Oxitocina/metabolismo , Urocortinas/administración & dosificación , Urocortinas/farmacología , Vasotocina/administración & dosificación , Vasotocina/análogos & derivados , Vasotocina/farmacologíaRESUMEN
Species have evolved diverse social behavior and mating strategies in response to selective forces in their environments. While promiscuity is the predominant mating strategy across most vertebrate taxa, convergent evolution of monogamous mating systems has occurred multiple times across distant lineages. Monogamous behavior is thought to be facilitated by a neurobiological capacity to form and maintain selective social attachments, or pair bonds, with a mating partner. The neural mechanisms of pair bonding behavior have been investigated most rigorously in Microtine rodents, which exhibit diverse social organizations. These studies have highlighted mesolimbic dopamine pathways, social neuropeptides (oxytocin and vasopressin), and other neural systems as integral factors in the formation, maintenance, and expression of pair bonds.
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Relapse triggered by drug-paired cues is a major obstacle for successful treatment of drug abuse. Patterns of brain activation induced by drug-paired cues have been identified in human and animal models, but lack of specificity poses a serious problem for craving or relapse interpretations. The goal of this study was to compare brain responses to contextual cues paired with a rewarding versus an aversive stimulus in a mouse model to test the hypothesis that different patterns of brain activation can be detected. Mice were trained to associate a common environmental context with an intraperitoneal injection of saline, lithium chloride or cocaine. After measuring each animal for conditioned place preference or aversion, mice were re-exposed to the context (CS+ or CS-) in absence of the reinforcer to analyze patterns of Fos expression in 10 brain regions chosen from previous literature. Levels of Fos in the cingulate cortex, paraventricular thalamic nucleus, paraventricular hypothalamic nucleus, and dentate gyrus differed in CS+ versus CS- groups, but the direction of the differences was the same for both lithium chloride (LiCl) and cocaine reinforcers. In the cingulate cortex, Fos was positively correlated with degree of place preference for cocaine or aversion to LiCl whereas in the periaqueductal gray the relationship was positive for LiCl and negative for cocaine. Results confirm Fos responses to reward- or aversion-paired cues are similar but specificity is detectable. Future studies are needed to comprehensively establish neuroanatomical specificity in conditioned responses to drugs as compared to other reinforcers.