BLA to vHPC Inputs Modulate Anxiety-Related Behaviors

The basolateral amygdala (BLA) and ventral hippocampus (vHPC) have both been implicated in mediating anxiety-related behaviors, but the functional contribution of BLA inputs to the vHPC has never been directly investigated. Here we show that activation of BLA-vHPC synapses acutely and robustly increased anxiety-related behaviors, while inhibition of BLA-vHPC synapses decreased anxiety-related behaviors. We combined optogenetic approaches with in vivo pharmacological manipulations and ex vivo whole-cell patch-clamp recordings to dissect the local circuit mechanisms, demonstrating that activation of BLA terminals in the vHPC provided monosynaptic, glutamatergic inputs to vHPC pyramidal neurons. Furthermore, BLA inputs exerted polysynaptic, inhibitory effects mediated by local interneurons in the vHPC that may serve to balance the circuit locally. These data establish a role for BLA-vHPC synapses in bidirectionally controlling anxiety-related behaviors in an immediate, yet reversible, manner and a model for the local circuit mechanism of BLA inputs in the vHPC.JPB FoundationPicower Institute for Learning and Memory (Innovation Fund)Whitehall FoundationEsther A. & Joseph Klingenstein Fund, Inc.Picower Institute for Learning and MemoryMassachusetts Institute of Technology. Department of Brain and Cognitive SciencesSwiss National Science Foundation. Postdoctoral Fellowship for Prospective Researchers (PBSKP3_143586)Howard Hughes Medical Institute (Undergraduate Education Grant)MIT Summer Research Progra

Inhibitory Input from the Lateral Hypothalamus to the Ventral Tegmental Area Disinhibits Dopamine Neurons and Promotes Behavioral Activation

Projections from the lateral hypothalamus (LH) to the ventral tegmental area (VTA), containing both GABAergic and glutamatergic components, encode conditioned responses and control compulsive reward-seeking behavior. GABAergic neurons in the LH have been shown to mediate appetitive and feeding-related behaviors. Here we show that the GABAergic component of the LH-VTA pathway supports positive reinforcement and place preference, while the glutamatergic component mediates place avoidance. In addition, our results indicate that photoactivation of these projections modulates other behaviors, such as social interaction and perseverant investigation of a novel object. We provide evidence that photostimulation of the GABAergic LH-VTA component, but not the glutamatergic component, increases dopamine (DA) release in the nucleus accumbens (NAc) via inhibition of local VTA GABAergic neurons. Our study clarifies how GABAergic LH inputs to the VTA can contribute to generalized behavioral activation across multiple contexts, consistent with a role in increasing motivational salience.National Institute of Mental Health (U.S.) (Grant R01-MH102441-01

Associative learning in auditory thalamus and amygdala

Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, September, 2019Manuscript.Includes bibliographical references.Although much pioneering work has furthered our understanding of the roles the medial geniculate nucleus of the thalamus (MGN) and basolateral amygdala (BLA) play in the formation of associative learning, many open questions remain. MGN is often thought of as only contributing relayed sensory information, and BLA the primary site of importance for the formation of associative learning, aspects of these assumptions have not been directly tested. It is known that both regions are necessary for learning to occur, but the current empirical understanding of the role MGN plays is lacking. Here we present circuit-specific characterization of the information MGN transmits to BLA during discriminative learning, using a combination of optogenetics and in vivo single unit electrophysiology. We demonstrate that while MGN may act as a relay station for information necessary for learning, this is an active process. This input also exhibits dynamic changes between conditions which can also be seen in the BLA population it projects onto. This provides strong evidence suggesting it plays an active role in learning, rather than the assumed role, restricted to sensory relay. Finally, we show that BLA encodes unavoidable punishment associations more strongly than avoidable punishment associations through a shift in the bias of difference encoding of these associations. Taken together, these findings suggest that the assumption of a sensory relay role for MGN in the formation of association central to current dogma is incomplete, and that the avoidability of an associated punishing outcome impacts the magnitude with which BLA encodes the bias between reward and punishment-associated tones.by Christopher Albert Leppla.Ph. D. in NeurosciencePh. D. in Neuroscience Massachusetts Institute of Technology, Department of Brain and Cognitive Science

Bidirectional modulation of anxiety-related and social behaviors by amygdala projections to the medial prefrontal cortex

The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) modulate anxiety and social behaviors. It remains to be elucidated, however, whether direct projections from the BLA to the mPFC play a functional role in these behaviors. We used optogenetic approaches in behaving mice to either activate or inhibit BLA inputs to the mPFC during behavioral assays that assess anxiety-like behavior and social interaction. Channelrhodopsin-2 (ChR2)-mediated activation of BLA inputs to the mPFC produced anxiogenic effects in the elevated plus maze and open field test, whereas halorhodopsin (NpHR)-mediated inhibition produced anxiolytic effects. Furthermore, activation of the BLA-mPFC pathway reduced social interaction in the resident-intruder test, whereas inhibition facilitated social interaction. These results establish a causal relationship between activity in the BLA-mPFC pathway and the bidirectional modulation of anxiety-related and social behaviors.National Institutes of Health (U.S.) (National Research Service Award Institutional Research Training Grant 5T32GM007484-38)Brain & Behavior Research Foundation (Young Investigator Award)National Institute of Mental Health (U.S.) (Research Supplement to Promote Diversity in Health-Related Sciences)Integrative Neuronal Systems FellowshipJames R. Killian FellowshipJPB FoundationWhitehall FoundationKlingenstein FoundationAlfred P. Sloan FoundationNew York Stem Cell FoundationNational Institutes of Health (U.S.) (R01-MH102441-01

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