Neuropeptidergic Control of an Internal Brain State Produced by Prolonged Social Isolation Stress

Prolonged periods of social isolation can generate an internal state that exerts profound effects on the brain and behavior. However, the neurobiological underpinnings of protracted social isolation have been relatively understudied. Here, we review recent literature implicating peptide neuromodulators in the establishment and maintenance of such internal states. More specifically, we describe an evolutionarily conserved role for the neuropeptide tachykinin in the control of social isolation–induced aggression and review recent data that elucidate the manner by which Tac2 controls the widespread effects of social isolation on behavior in mice. Last, we discuss potential roles for additional neuromodulators in controlling social isolation and a more general role for Tac2 in the response to other forms of stress

Neuropeptidergic Control of an Internal Brain State Produced by Prolonged Social Isolation Stress

Prolonged periods of social isolation can generate an internal state that exerts profound effects on the brain and behavior. However, the neurobiological underpinnings of protracted social isolation have been relatively understudied. Here, we review recent literature implicating peptide neuromodulators in the establishment and maintenance of such internal states. More specifically, we describe an evolutionarily conserved role for the neuropeptide tachykinin in the control of social isolation–induced aggression and review recent data that elucidate the manner by which Tac2 controls the widespread effects of social isolation on behavior in mice. Last, we discuss potential roles for additional neuromodulators in controlling social isolation and a more general role for Tac2 in the response to other forms of stress

Isomorphisms between psychological processes and neural mechanisms: From stimulus elements to genetic markers of activity

Traditional learning theory has developed models that can accurately predict and describe the course of learned behavior. These “psychological process” models rely on hypothetical constructs that are usually thought to be not directly measurable or manipulable. Recently, and mostly in parallel, the neural mechanisms underlying learning have been fairly well elucidated. The argument in this essay is that we can successfully uncover isomorphisms between process and mechanism and that this effort will help advance our theories about both processes and mechanisms. We start with a brief review of error-correction circuits as a successful example. Then we turn to the concept of stimulus elements, where the conditional stimulus is hypothesized to be constructed of a multitude of elements only some of which are sampled during any given experience. We discuss such elements with respect to how they explain acquisition of associative strength as an incremental process. Then we propose that for fear conditioning, stimulus elements and basolateral amygdala projection neurons are isomorphic and that the activational state of these “elements” can be monitored by the expression of the mRNA for activity-regulated cytoskeletal protein (ARC). Finally we apply these ideas to analyze recent data examining ARC expression during contextual fear conditioning and find that there are indeed many similarities between stimulus elements and amygdala neurons. The data also suggest some revisions in the conceptualization of how the population of stimulus elements is sampled from

Ventromedial hypothalamic neurons control a defensive emotion state

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

The Mouse Action Recognition System (MARS): a software pipeline for automated analysis of social behaviors in mice

The study of social behavior requires scoring the animals' interactions. This is generally done by hand-- a time consuming, subjective, and expensive process. Recent advances in computer vision enable tracking the pose (posture) of freely-behaving laboratory animals automatically. However, classifying complex social behaviors such as mounting and attack remains technically challenging. Furthermore, the extent to which expert annotators, possibly from different labs, agree on the definitions of these behaviors varies. There is a shortage in the neuroscience community of benchmark datasets that can be used to evaluate the performance and reliability of both pose estimation tools and manual and automated behavior scoring. We introduce the Mouse Action Recognition System (MARS), an automated pipeline for pose estimation and behavior quantification in pairs of freely behaving mice. We compare MARS's annotations to human annotations and find that MARS's pose estimation and behavior classification achieve human-level performance. As a by-product we characterize the inter-expert variability in behavior scoring. The two novel datasets used to train MARS were collected from ongoing experiments in social behavior, and identify the main sources of disagreement between annotators. They comprise 30,000 frames of manual annotated mouse poses and over 14 hours of manually annotated behavioral recordings in a variety of experimental preparations. We are releasing this dataset alongside MARS to serve as community benchmarks for pose and behavior systems. Finally, we introduce the Behavior Ensemble and Neural Trajectory Observatory (Bento), a graphical interface that allows users to quickly browse, annotate, and analyze datasets including behavior videos, pose estimates, behavior annotations, audio, and neural recording data. We demonstrate the utility of MARS and Bento in two use cases: a high-throughput behavioral phenotyping study, and exploration of a novel imaging dataset. 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

The Mouse Action Recognition System (MARS): a software pipeline for automated analysis of social behaviors in mice

The study of social behavior requires scoring the animals' interactions. This is generally done by hand-- a time consuming, subjective, and expensive process. Recent advances in computer vision enable tracking the pose (posture) of freely-behaving laboratory animals automatically. However, classifying complex social behaviors such as mounting and attack remains technically challenging. Furthermore, the extent to which expert annotators, possibly from different labs, agree on the definitions of these behaviors varies. There is a shortage in the neuroscience community of benchmark datasets that can be used to evaluate the performance and reliability of both pose estimation tools and manual and automated behavior scoring. We introduce the Mouse Action Recognition System (MARS), an automated pipeline for pose estimation and behavior quantification in pairs of freely behaving mice. We compare MARS's annotations to human annotations and find that MARS's pose estimation and behavior classification achieve human-level performance. As a by-product we characterize the inter-expert variability in behavior scoring. The two novel datasets used to train MARS were collected from ongoing experiments in social behavior, and identify the main sources of disagreement between annotators. They comprise 30,000 frames of manual annotated mouse poses and over 14 hours of manually annotated behavioral recordings in a variety of experimental preparations. We are releasing this dataset alongside MARS to serve as community benchmarks for pose and behavior systems. Finally, we introduce the Behavior Ensemble and Neural Trajectory Observatory (Bento), a graphical interface that allows users to quickly browse, annotate, and analyze datasets including behavior videos, pose estimates, behavior annotations, audio, and neural recording data. We demonstrate the utility of MARS and Bento in two use cases: a high-throughput behavioral phenotyping study, and exploration of a novel imaging dataset. 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

The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress

Chronic social isolation causes severe psychological effects in humans, but their neural bases remain poorly understood. 2 weeks (but not 24 hr) of social isolation stress (SIS) caused multiple behavioral changes in mice and induced brain-wide upregulation 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

The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress

Chronic social isolation causes severe psychological effects in humans, but their neural bases remain poorly understood. 2 weeks (but not 24 hr) of social isolation stress (SIS) caused multiple behavioral changes in mice and induced brain-wide upregulation 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

Alpha-synuclein pathology, microgliosis, and parvalbumin neuron loss in the amygdala associated with enhanced fear in the Thy1-aSyn model of Parkinson's disease

In Parkinson's disease (PD), the second most common neurodegenerative disorder, non-motor symptoms often precede the development of debilitating motor symptoms and present a severe impact on the quality of life. Lewy bodies containing misfolded α-synuclein progressively develop in neurons throughout the peripheral and central nervous system, which may be correlated with the early development of non-motor symptoms. Among those, increased fear and anxiety is frequent in PD and thought to result from pathology outside the dopaminergic system, which has been the focus of symptomatic treatment to alleviate motor symptoms. Alpha-synuclein accumulation has been reported in the amygdala of PD patients, a brain region critically involved in fear and anxiety. Here we asked whether α-synuclein overexpression alone is sufficient to induce an enhanced fear phenotype in vivo and which pathological mechanisms are involved. Transgenic mice expressing human wild-type α-synuclein (Thy1-aSyn), a well-established model of PD, were subjected to fear conditioning followed by extinction and then tested for extinction memory retention followed by histopathological analysis. Thy1-aSyn mice showed enhanced tone fear across acquisition and extinction compared to wild-type littermates, as well as a trend to less retention of fear extinction. Immunohistochemical analysis of the basolateral nucleus of the amygdala, a nucleus critically involved in tone fear learning, revealed extensive α-synuclein pathology, with accumulation, phosphorylation, and aggregation of α-synuclein in transgenic mice. This pathology was accompanied by microgliosis and parvalbumin neuron loss in this nucleus, which could explain the enhanced fear phenotype. Importantly, this non-motor phenotype was detected in the pre-clinical phase, prior to dopamine loss in Thy1-aSyn mice, thus replicating observations in patients. Results obtained in this study suggest a possible mechanism by which increased anxiety and maladaptive fear processing may occur in PD, opening a door for therapeutic options and further early biomarker research