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Chronic social isolation causes severe psychological effects in humans, but their neural bases remains poorly understood. Two weeks (but not 24 hrs) of social isolation stress (SIS) caused multiple behavioral changes in mice, and induced brain-wide up-regulation of the neuropeptide tachykinin 2 (Tac2)/neurokinin B (NkB). Systemic administration of an Nk3R antagonist prevented virtually all of the behavioral effects of chronic SIS. Conversely, enhancing NkB expression and release phenocopied SIS in group-housed mice, promoting aggression and converting stimulus-locked defensive behaviors to persistent responses. Multiplexed analysis of Tac2/NkB function in multiple brain areas revealed dissociable, region-specific requirements for both the peptide and its receptor in different SIS-induced behavioral changes. Thus, Tac2 coordinates a pleiotropic brain state caused by SIS, via a distributed mode of action. These data reveal the profound effects of prolonged social isolation on brain chemistry and function, and suggest potential new therapeutic applications for Nk3R antagonists.

A lack of automated, quantitative, and accurate assessment of social behaviors in mammalian animal models has limited progress toward understanding mechanisms underlying social interactions and their disorders such as autism. Here we present a new integrated hardware and software system that combines video tracking, depth sensing, and machine learning for automatic detection and quantification of social behaviors involving close and dynamic interactions between two mice of different coat colors in their home cage. We designed a hardware setup that integrates traditional video cameras with a depth camera, developed computer vision tools to extract the body "pose" of individual animals in a social context, and used a supervised learning algorithm to classify several well-described social behaviors. We validated the robustness of the automated classifiers in various experimental settings and used them to examine how genetic background, such as that of Black and Tan Brachyury (BTBR) mice (a previously reported autism model), influences social behavior. Our integrated approach allows for rapid, automated measurement of social behaviors across diverse experimental designs and also affords the ability to develop new, objective behavioral metrics.

SummaryAll animals possess a repertoire of innate (or instinctive1,2) behaviors, which can be performed without training. Whether such behaviors are mediated by anatomically distinct and/or genetically specified neural pathways remains a matter of debate3-5. Here we report that hypothalamic neural ensemble representations underlying innate social behaviors are shaped by social experience. Estrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) control mating and fighting in rodents6-8. We used microendoscopy9 to image VMHvl Esr1+ neuronal activity in male mice engaged in these social behaviours. In sexually and socially experienced adult males, divergent and characteristic neural ensembles represented male vs. female conspecifics. But surprisingly, in inexperienced adult males, male and female intruders activated overlapping neuronal populations. Sex-specific ensembles gradually separated as the mice acquired social and sexual experience. In mice permitted to investigate but not mount or attack conspecifics, ensemble divergence did not occur. However, 30 min of sexual experience with a female was sufficient to promote both male vs. female ensemble separation and attack, measured 24 hr later. These observations uncover an unexpected social experience-dependent component to the formation of hypothalamic neural assemblies controlling innate social behaviors. More generally, they reveal plasticity and dynamic coding in an evolutionarily ancient deep subcortical structure that is traditionally viewed as a “hard-wired” system.

Defensive behaviors reflect underlying emotion states, such as fear. The hypothalamus plays a role in such behaviors, but prevailing textbook views depict it as an effector of upstream emotion centers, such as the amygdala, rather than as an emotion center itself. We used optogenetic manipulations to probe the function of a specific hypothalamic cell type that mediates innate defensive responses. These neurons are sufficient to drive multiple defensive actions, and required for defensive behaviors in diverse contexts. The behavioral consequences of activating these neurons, moreover, exhibit properties characteristic of emotion states in general, including scalability, (negative) valence, generalization and persistence. Importantly, these neurons can also condition learned defensive behavior, further refuting long-standing claims that the hypothalamus is unable to support emotional learning and therefore is not an emotion center. These data indicate that the hypothalamus plays an integral role to instantiate emotion states, and is not simply a passive effector of upstream emotion centers.DOI: http://dx.doi.org/10.7554/eLife.06633.001

The study of naturalistic social behavior requires quantification of animals’ interactions. This is generally done through manual annotation—a highly time-consuming and tedious process. Recent advances in computer vision enable tracking the pose (posture) of freely behaving animals. However, automatically and accurately classifying complex social behaviors remains technically challenging. We introduce the Mouse Action Recognition System (MARS), an automated pipeline for pose estimation and behavior quantification in pairs of freely interacting mice. We compare MARS’s annotations to human annotations and find that MARS’s pose estimation and behavior classification achieve human-level performance. We also release the pose and annotation datasets used to train MARS to serve as community benchmarks and resources. Finally, we introduce the Behavior Ensemble and Neural Trajectory Observatory (BENTO), a graphical user interface for analysis of multimodal neuroscience datasets. Together, MARS and BENTO provide an end-to-end pipeline for behavior data extraction and analysis in a package that is user-friendly and easily modifiable.

Specific brain circuits have been classically linked to dedicated functions. However, compensation following brain damage suggests that these circuits are capable of dynamic adaptation. Such compensation is exemplified by Pavlovian fear conditioning following damage to the dorsal hippocampus (DH). Although the DH normally underlies contextual fear and fear renewal after extinction, both can be learned in the absence of the DH, although the mechanisms and nature of this compensation are currently unknown. Here, we report that recruitment of alternate structures, specifically the infralimbic and prelimbic prefrontal cortices, is required for compensation following damage to the hippocampus. Disconnection of these cortices in DH-compromised animals and immediate early gene induction profiles for amygdala-projecting prefrontal cells revealed that communication and dynamic rebalancing within this prefrontal microcircuit is critical. Additionally, the infralimbic cortex normally plays a role in limiting generalization of contextual fear. These discoveries reveal that plasticity through recruitment of alternate circuits allows the brain to compensate following damage, offering promise for targeted treatment of memory disorders.anxiety | recovery of function | amnesia | medial prefrontal cortex A widely accepted view is that the brain is comprised of multiple independent circuits dedicated to performing specific functions and encoding specific information. This view is exemplified in the field of learning and memory, where it is held that different circuits specialize in integrating and storing different classes of memories (1). However, studies looking at learning following brain damage clearly demonstrate that the brain can also behave dynamically. For example, in Pavlovian fear conditioning, contextual memories can be formed in the absence of circuits classically thought to underpin integration and storage of information about an animal's environment or context (2).In fear conditioning, contexts play two key roles in controlling fear learning and expression. First, a context can act as a conditional stimulus (CS), to which fear can be directly conditioned when an aversive experience, such as a foot shock [unconditional stimulus (US)] is signaled by the context. Second, contexts can modulate responding to a discrete cue, such as a tone-CS, which has acquired multiple meanings. For example, in extinction, a tone previously conditioned to elicit fear is presented in the absence of the aversive foot shock US, such that the conditional fear response begins to extinguish. However, because extinction is not an erasure of the original fear but rather new learning that interferes with retrieval of the original fear memory, an extinguished cue has multiple meanings (shock/no shock), which compete for behavioral expression (3). This competition is mediated by context, as fear renewal occurs when an extinguished stimulus is presented outside of the extinction context (4).These context-sensitive effects provide excellent models t...

Although the circuit mediating contextual fear conditioning has been extensively described, the precise contribution that specific anatomical nodes make to behavior has not been fully elucidated. To clarify the roles of the dorsal hippocampus (DH), basolateral amygdala (BLA), and medial prefrontal cortex (mPFC) in contextual fear conditioning, activity within these regions was mapped using cellular compartment analysis of temporal activity using fluorescence in situ hybridization (catFISH) for Arc mRNA. Rats were delay-fear conditioned or immediately shocked (controls) and thereafter reexposed to the shocked context to test for fear memory recall. Subsequent catFISH analyses revealed that in the DH, cells were preferentially reactivated during the context test, regardless of whether animals had been fear conditioned or immediately shocked, suggesting that the DH encodes spatial information specifically, rather then the emotional valence of an environment. In direct contrast, neuronal ensembles in the BLA were only reactivated at test if animals had been fear conditioned, suggesting that the amygdala specifically tracks the emotional properties of a context. Interestingly, Arc expression in the mPFC was consistent with both amygdala-and hippocampus-like patterns, supporting a role for the mPFC in both fear and contextual processing. Collectively, these data provide crucial insight into the region-specific behavior of neuronal ensembles during contextual fear conditioning and demonstrate a dissociable role for the hippocampus and amygdala in processing the contextual and emotional properties of a fear memory.