Clarifying the neural circuit mechanisms of spontaneous social behavior in macaques.

Stimulation of medial amygdala GABA neurons with kinetically different channelrhodopsins yields opposite behavioral outcomes.

In 2006, research on the neurotransmitter serotonin and its transporter protein (5‐HTT) in the synaptic gap celebrated a series of anniversaries. Forty‐five years earlier, presynaptic neurotransmitter uptake was discovered (Hertting & Axelrod, 1961). Two decades later, 5‐HTT was first linked to depression (Langer et al , 1981), shortly after its identification as a target of antidepressant drugs (Raisman et al , 1979). The sequence of the transporter gene from rats was published 10 years after that (Blakely et al , 1991), which initiated an avalanche of molecular genetic studies on the regulation of emotionality. This research culminated in two reports revealing an association between variations of the 5‐HTT gene ( 5‐HTT and SLC6A4 ) and anxiety‐related traits as well as depression (Collier et al , 1996; Lesch et al , 1996). Since then, clinical studies have further supported the link between variants of 5‐HTT and disorders in the regulation of emotion. Although modest effect sizes—typical of non‐Mendelian traits—polygenic patterns of inheritance, epistatic and epigenetic interactions, and heterogeneity between studies confounded the results, 5‐HTT comprises a model molecule for studying gene–environment interactions in cognitive and psychiatric neuroscience. The demonstration in rhesus macaques that stress early in life uniquely reinforces links between variations of 5‐HTT , behaviour and psychopathology seems to herald in a new era of behavioural genetics. Moreover, the discovery that 5‐HTT is a susceptibility gene for depression is a first step towards explaining the molecular dimensions of personality and behaviour, identifying physiological pathways that lead to other disorders of cognitive function and emotion, and analysing the interactive effects of genes and environment in the development of disease. On the heels of these results from behavioural genetics, novel approaches including neurophysiology, neuropsychology and functional neuroimaging, as well as the inclusion of other phenotypes (such as higher cognitive functions, communication skills, social competence and longevity), have …

Oxytocin (OT), a neuropeptide that acts in the brain as a neuromodulator, has been long known to shape maternal physiology and behavior in mammals, however its role in regulating social cognition and behavior in primates has come to the forefront only in the recent decade. Many of the current perspectives on the role of OT in modulating social behavior emerged first from studies in rodents, where invasive techniques with a high degree of precision have permitted the mechanistic dissection of OT-related behaviors, as well as their underlying neural circuits in exquisite detail. In parallel, behavioral and imaging studies in humans have suggested that brain OT may similarly influence human social behavior and neural activity. These studies in rodents and humans have spurred interest in the therapeutic potential of targeting the OT system to remedy deficits in social cognition and behavior that are present across numerous psychiatric disorders. Yet there remains a tremendous gap in our mechanistic understanding of the influence of brain OT on social neural circuitry between rodents and man. In fact, very little is known regarding the neural mechanisms by which exogenous or endogenous OT influences human social cognition, limiting its therapeutic potential. Here we discuss how non-human primates (NHPs) are uniquely positioned to now bridge the gaps in knowledge provided by the precise circuit-level approaches widely used in rodent models and the behavioral, imaging, and clinical studies in humans. This review provides a perspective on what has been achieved, and what can be expected from exploring the role of OT in shaping social behaviors in NHPs in the coming years.

The dorsal medial prefrontal cortex and basolateral amygdala exhibit social behavior-relevant neuronal oscillations, representing unified pathophysiological mechanisms underlying social behavioral deficits.

The dorsal medial prefrontal cortex and basolateral amygdala exhibit social behavior-relevant neuronal oscillations, representing unified pathophysiological mechanisms underlying social behavioral deficits.

Social behaviors, how individuals act cooperatively and competitively with conspecifics, are widely seen across species. Rodents display various social behaviors, and many different behavioral paradigms have been used for investigating their neural circuit bases. Social behavior is highly vulnerable to brain network dysfunction caused by neurological and neuropsychiatric conditions such as autism spectrum disorders (ASDs). Studying mouse models of ASD provides a promising avenue toward elucidating mechanisms of abnormal social behavior and potential therapeutic targets for treatment. In this review, we outline recent progress and key findings on neural circuit mechanisms underlying social behavior, with particular emphasis on rodent studies that monitor and manipulate the activity of specific circuits using modern systems neuroscience approaches. Social behavior is mediated by a distributed brain-wide network among major cortical (e.g., medial prefrontal cortex (mPFC), anterior cingulate cortex, and insular cortex (IC)) and subcortical (e.g., nucleus accumbens, basolateral amygdala (BLA), and ventral tegmental area) structures, influenced by multiple neuromodulatory systems (e.g., oxytocin, dopamine, andserotonin). We particularly draw special attention to IC as a unique cortical area that mediates multisensory integration, encoding of ongoing social interaction, social decision-making, emotion, and empathy. Additionally, a synthesis of studies investigating ASD mouse models demonstrates that dysfunctions in mPFC-BLA circuitry and neuromodulation are prominent. Pharmacological rescues by local or systemic (e.g., oral) administration of various drugs have provided valuable clues for developing new therapeutic agents for ASD. Future efforts and technological advances will push forward the next frontiers in this field, such as the elucidation of brain-wide network activity and inter-brain neural dynamics during real and virtual social interactions, and the establishment of circuit-based therapy for disorders affecting social functions.

Psychiatric disorders are highly heritable pathologies of altered neural circuit functioning. How genetic mutations lead to specific neural circuit abnormalities underlying behavioral disruptions, however, remains unclear. Using circuit-selective transgenic tools and a mouse model of maladaptive social behavior (ArpC3 mutant), we identify a neural circuit mechanism driving dysfunctional social behavior. We demonstrate that circuit-selective knockout (ctKO) of the ArpC3 gene within prefrontal cortical neurons that project to the basolateral amygdala elevates the excitability of the circuit neurons, leading to disruption of socially evoked neural activity and resulting in abnormal social behavior. Optogenetic activation of this circuit in wild-type mice recapitulates the social dysfunction observed in ArpC3 mutant mice. Finally, the maladaptive sociability of ctKO mice is rescued by optogenetically silencing neurons within this circuit. These results highlight a mechanism of how a gene-to-neural circuit interaction drives altered social behavior, a common phenotype of several psychiatric disorders.

Dr. Munir “Gunes” Kutlu, Assistant Professor at the Center for Substance Abuse Research (CSAR) and the Department of Neural Sciences at Temple University Lewis Katz School of Medicine, investigates the neural mechanisms underlying associative learning, mainly focusing on reward, fear, and social interaction. Drawing from his computational neuroscience training at Duke University and postdoctoral work at Temple and Vanderbilt Universities, Dr. Kutlu combines systems neuroscience, computational approaches, and behavioral analysis to understand how our brains process environmental associations and how these processes can become maladaptive in disease states. His laboratory, dedicated to “bridging the brain-behavior gap,” fosters a collaborative environment that nurtures the next generation of neuroscientists while pursuing innovative neural circuit analysis approaches in reward and aversive learning contexts. In this Genomic Press interview, Dr. Kutlu shares his insights on these fascinating aspects of behavioral neuroscience and his laboratory's mission to advance our understanding of neural circuit function in health and disease.

A Neural Circuit Mechanism Integrating Motivational State with Memory Expression in Drosophila

Infant isoflurane exposure affects social behaviours, but does not impair specific cognitive domains in juvenile non-human primates

The Polyvagal theory proposes the Social Engagement System as a theoretical model linking social behavior with the neural regulation of the heart (via the vagus) and the striated muscles of the face and head (via special visceral efferent pathways). The current pilot study tested the feasibility of this model with typically developing 3-5-year-old children by evaluating the relation between spontaneous social engagement behavior measured by eye gaze behaviors and the visceromotor (e.g., respiratory sinus arrhythmia) and somatomotor (e.g., right tympanic membrane compliance) components of the Social Engagement System. Regression analyses supported the hypothesis that the visceromotor and somatomotor components of the Social Engagement System significantly predict social behavior (indexed by spontaneous eye gazes). Future studies assessing indices of visceral regulation and middle ear muscle function may provide insights into neural mechanisms mediating features of developmental disorders, such as autism, that have deficits in spontaneous eye gaze, auditory processing, and social behavior.

Neural circuits of social behaviors: Innate yet flexible

Prefrontal Regulation of Social Behavior and Related Deficits: Insights From Rodent Studies

SummarySocial behavior is widespread in the animal kingdom, and it remarkably influences human personal and professional lives. However, a thorough understanding of the mechanisms underlying social behavior is elusive. Integrating the seemingly different fields of robotics and preclinical research could bring new insight on social behavior. Toward this aim, we established “behavioral teleporting” as an experimental solution to independently manipulate multiple factors underpinning social interactions. Behavioral teleporting consists of real-time transfer of the complete ethogram of a live zebrafish onto a remotely-located robotic replica. Through parallel and simultaneous behavioral teleporting, we studied the interaction between two live fish swimming in remotely-located tanks: each live fish interacted with an inanimate robot that mirrored the behavior of the other fish, and the morphology of each robot was independently tailored. Our results indicate that behavioral teleporting can preserve natural interaction between two live animals, while allowing fine control over morphological features that modulate social behavior.

Methylphenidate is the first-choice treatment for attention-deficit/hyperactivity disorder (ADHD), but its mechanism of action is incompletely understood. The cognitive effects of methylphenidate have been extensively studied, but little is known about its effects on spontaneous social behavior. During adolescence, rats display a characteristic, highly vigorous form of social behavior, termed social play behavior, which is of critical importance for social and cognitive development. We investigated the neurobehavioral mechanisms by which methylphenidate affects social play behavior in rats. Methylphenidate (0.3-3.0 mg/kg, s.c. or p.o.) abolished social play behavior, without altering general social interest. This effect of methylphenidate did not depend upon the baseline level of social play and was not secondary to changes in locomotion. Furthermore, the play-suppressant effect of methylphenidate was not subject to tolerance or sensitization. Methylphenidate blocked both the initiation to play and the responsivity to play initiation. The effect of methylphenidate was mimicked by the noradrenaline reuptake inhibitor atomoxetine, which is also used for the treatment of ADHD, and was blocked by an alpha-2 adrenoceptor antagonist. In addition, combined administration of subeffective doses of methylphenidate and atomoxetine suppressed social play. However, blockade of alpha-1 adrenoceptors, beta-adrenoceptors, or dopamine receptors did not alter the effect of methylphenidate. These data show that methylphenidate selectively blocks the most vigorous part of the behavioral repertoire of adolescent rats through a noradrenergic mechanism. We suggest that the effect of methylphenidate on social play is a reflection of its therapeutic effect in ADHD, that is, improved behavioral inhibition. However, given the importance of social play for development, these findings may also indicate an adverse side effect of methylphenidate.