Optogenetic insights on the relationship between anxiety-related behaviors and social deficits

Many psychiatric illnesses are characterized by deficits in the social domain. For example, there is a high rate of co-morbidity between autism spectrum disorders and anxiety disorders. However, the common neural circuit mechanisms by which social deficits and other psychiatric disease states, such as anxiety, are co-expressed remains unclear. Here, we review optogenetic investigations of neural circuits in animal models of anxiety-related behaviors and social behaviors and discuss the important role of the amygdala in mediating aspects of these behaviors. In particular, we focus on recent evidence that projections from the basolateral amygdala (BLA) to the ventral hippocampus (vHPC) modulate anxiety-related behaviors and also alter social interaction. Understanding how this circuit influences both social behavior and anxiety may provide a mechanistic explanation for the pathogenesis of social anxiety disorder, as well as the prevalence of patients co-diagnosed with autism spectrum disorders and anxiety disorders. Furthermore, elucidating how circuits that modulate social behavior also mediate other complex emotional states will lead to a better understanding of the underlying mechanisms by which social deficits are expressed in psychiatric disease

Estimating a Separably Markov Random Field from Binary Observations

A fundamental problem in neuroscience is to characterize the dynamics of spiking from the neurons in a circuit that is involved in learning about a stimulus or a contingency. A key limitation of current methods to analyze neural spiking data is the need to collapse neural activity over time or trials, which may cause the loss of information pertinent to understanding the function of a neuron or circuit. We introduce a new method that can determine not only the trial-to-trial dynamics that accompany the learning of a contingency by a neuron, but also the latency of this learning with respect to the onset of a conditioned stimulus. The backbone of the method is a separable two-dimensional (2D) random field (RF) model of neural spike rasters, in which the joint conditional intensity function of a neuron over time and trials depends on two latent Markovian state sequences that evolve separately but in parallel. Classical tools to estimate state-space models cannot be applied readily to our 2D separable RF model. We develop efficient statistical and computational tools to estimate the parameters of the separable 2D RF model. We apply these to data collected from neurons in the prefrontal cortex in an experiment designed to characterize the neural underpinnings of the associative learning of fear in mice. Overall, the separable 2D RF model provides a detailed, interpretable characterization of the dynamics of neural spiking that accompany the learning of a contingency.National Institute of Mental Health (U.S.) (Grant R01-MH102441-01)National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (Award DP2-DK-102256-01)National Institute on Aging (Grant RF1- AG047661-01

Decoding Neural Circuits that Control Compulsive Sucrose Seeking

The lateral hypothalamic (LH) projection to the ventral tegmental area (VTA) has been linked to reward processing, but the computations within the LH-VTA loop that give rise to specific aspects of behavior have been difficult to isolate. We show that LH-VTA neurons encode the learned action of seeking a reward, independent of reward availability. In contrast, LH neurons downstream of VTA encode reward-predictive cues and unexpected reward omission. We show that inhibiting the LH-VTA pathway reduces “compulsive” sucrose seeking but not food consumption in hungry mice. We reveal that the LH sends excitatory and inhibitory input onto VTA dopamine (DA) and GABA neurons, and that the GABAergic projection drives feeding-related behavior. Our study overlays information about the type, function, and connectivity of LH neurons and identifies a neural circuit that selectively controls compulsive sugar consumption, without preventing feeding necessary for survival, providing a potential target for therapeutic interventions for compulsive-overeating disorder.JPB FoundationWhitehall FoundationKlingenstein FoundationBrain & Behavior Research Foundation (Young Investigator Award)Alfred P. Sloan FoundationNational Institute of Mental Health (U.S.) (NIH R01-MH102441-01)National Institutes of Health (U.S.) (Director’s New Investigator Award DP2-DK-102256-01)National Science Foundation (U.S.). Graduate Research FellowshipIntegrative Neuronal Systems FellowshipTraining Program in the Neurobiology of Learning and MemoryMassachusetts Institute of Technology. Simons Center for the Social Brain (Postdoctoral Fellowship)Jeffrey and Nancy Halis FellowshipHenry E. Singleton FundJames R. Killian FellowshipNWO of the Netherlands (Rubicon Award

Corticoamygdala Transfer of Socially Derived Information Gates Observational Learning

Observational learning is a powerful survival tool allowing individuals to learn about threat-predictive stimuli without directly experiencing the pairing of the predictive cue and punishment. This ability has been linked to the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA). To investigate how information is encoded and transmitted through this circuit, we performed electrophysiological recordings in mice observing a demonstrator mouse undergo associative fear conditioning and found that BLA-projecting ACC (ACC→BLA) neurons preferentially encode socially derived aversive cue information. Inhibition of ACC→BLA alters real-time amygdala representation of the aversive cue during observational conditioning. Selective inhibition of the ACC→BLA projection impaired acquisition, but not expression, of observational fear conditioning. We show that information derived from observation about the aversive value of the cue is transmitted from the ACC to the BLA and that this routing of information is critically instructive for observational fear conditioning. Video Abstract: [Figure presented] For an individual to watch another's experience and learn from it, signals need to move from cortical neurons to the basolateral amygdala during detection and integration of the necessary social cues.NIMH (Grant R01-MH102441-01)NIA (Grant RF1-AG047661-01)NIDDK (Award DP2-DK-102256-01)NCCIH (Grant DP1-AT009925)NIH (Grants 1-R01-AG-050548-01, DP1-OD003646 and R01-GM104948