Optogenetic dissection of neural circuits underlying emotional valence and motivated behaviors

The neural circuits underlying emotional valence and motivated behaviors are several synapses away from both defined sensory inputs and quantifiable motor outputs. Electrophysiology has provided us with a suitable means for observing neural activity during behavior, but methods for controlling activity for the purpose of studying motivated behaviors have been inadequate: electrical stimulation lacks cellular specificity and pharmacological manipulation lacks temporal resolution. The recent emergence of optogenetic tools provides a new means for establishing causal relationships between neural activity and behavior. Optogenetics, the use of genetically-encodable light-activated proteins, permits the modulation of specific neural circuit elements with millisecond precision. The ability to control individual cell types, and even projections between distal regions, allows us to investigate functional connectivity in a causal manner. The greatest consequence of controlling neural activity with finer precision has been the characterization of individual neural circuits within anatomical brain regions as defined functional units. Within the mesolimbic dopamine system, optogenetics has helped separate subsets of dopamine neurons with distinct functions for reward, aversion and salience processing, elucidated GABA neuronal effects on behavior, and characterized connectivity with forebrain and cortical structures. Within the striatum, optogenetics has confirmed the opposing relationship between direct and indirect pathway medium spiny neurons (MSNs), in addition to characterizing the inhibition of MSNs by cholinergic interneurons. Within the hypothalamus, optogenetics has helped overcome the heterogeneity in neuronal cell-type and revealed distinct circuits mediating aggression and feeding. Within the amygdala, optogenetics has allowed the study of intra-amygdala microcircuitry as well as interconnections with distal regions involved in fear and anxiety. In this review, we will present the body of optogenetic studies that has significantly enhanced our understanding of emotional valence and motivated behaviors.Picower Institute for Learning and Memory (Innovation Fund)Whitehall Foundation (2012-08-45)Wade AwardPicower Neurological Disorder Research FundNational Science Foundation (U.S.). Graduate Research Fellowship ProgramIntegrative Neuronal Systems Center (Grant 6926328)Brain and Cognitive Sciences Special Award (1497200)Marcus Fellowship to Honor Norman B. Leventhal (3891441

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

LH control of motivated behaviors through the midbrain dopamine system

Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2016.Cataloged from PDF version of thesis.Includes bibliographical references (pages 209-231).The lateral hypothalamus and ventral tegmental area are two brain regions that have long been known to be involved in processing reward and the control of feeding behaviors. We continue work in this area by identifying the functional connectivity between these two regions, providing evidence that LH neurons projecting to the VTA encode conditioned responses, while LH neurons innervated by the VTA encode conditioned and unconditioned stimuli. Activation of the LH-VTA projection can increase compulsive sugar seeking, while inhibition of the projection can suppress this behavior without altering normal feeding due to hunger. We can separate this projection into the GABAergic and glutamatergic components, and we show that the GABAergic component plays a role in promoting feeding and social interaction by increasing motivation for consummatory behaviors, while the glutamatergic component largely plays a role in the suppression of these behaviors. Finally, we show that activation of the GABAergic component causes dopamine release downstream in the nucleus accumbens via disinhibition of VTA dopamine neurons through VTA GABA neurons. Together, these experiments have profoundly elucidated the functional roles of the individual circuit components of the greater mesolimbic dopamine system and provided potential targets for therapeutic intervention of overeating disorders and obesity..by Edward H. Nieh.Ph. D. in Neuroscienc

Homeostasis Meets Motivation in the Battle to Control Food Intake

Signals of energy homeostasis interact closely with neural circuits of motivation to control food intake. An emerging hypothesis is that the transition to maladaptive feeding behavior seen in eating disorders or obesity may arise from dysregulation of these interactions. Focusing on key brain regions involved in the control of food intake (ventral tegmental area, striatum, hypothalamus, and thalamus), we describe how activity of specific cell types embedded within these regions can influence distinct components of motivated feeding behavior. We review how signals of energy homeostasis interact with these regions to influence motivated behavioral output and present evidence that experience-dependent neural adaptations in key feeding circuits may represent cellular correlates of impaired food intake control. Future research into mechanisms that restore the balance of control between signals of homeostasis and motivated feeding behavior may inspire new treatment options for eating disorders and obesity

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