Reward and associative learning processes guide future behaviors based on previous outcomes in similar settings. These processes are essential to survival as they increase the probability of obtaining rewards and avoiding negative stimuli. Associative learning is dysregulated in a wide array of neuropsychiatric disease states including depression, eating disorders, schizophrenia, and many others. Thus, understanding the neural mechanisms controlling associative learning processes is paramount to designing rationale, efficacious pharmacotherapeutic treatment strategies to ameliorate pathological aberrations in reward learning. Two brain regions, the basolateral amygdala (BLA) and lateral hypothalamus (LH), have both separately implicated in encoding information concerning rewards and the stimuli that predict their availability. These two regions are connected anatomically by an afferent projection from the BLA to LH, however, there is a paucity of investigations into this pathway, and its function remains obscure. Our preliminary data demonstrate that animals will nose poke for stimulation of the BLA to LH pathway indicating that the stimulation of this pathway is rewarding/reinforcing. We hypothesize that endogenous activation of this pathway may imbue reward predicative stimuli with motivational value, and thereby represent a critical neural substrate for encoding of associative learning.
The specific aims proposed in this application will systemically test the hypothesis that the BLA to LH projection is encoding the relationship between expected and actual outcomes during reward learning. We will integrate cutting-edge calcium imaging technologies with pathway-specific viral expression of calcium indicators to record the endogenous activity of this pathway during discrete aspects of reward learning. We will then use optogenetic approaches to occlude signaling of this pathway in a temporally specific manner to determine if this signaling is necessary for reward learning. The innovative integration of these cutting-edge experimental approaches will allow us to, for the first time, determine the temporally specific activity in this pathway that encodes reward value. A successful outcome of the proposed experiments will greatly advance out understanding of associative learning processes, and may help to drive the design of novel pharmacotherapeutic treatment strategies.
The ability to associate positive and negative outcomes with cues that predict their occurrence is critical for survival, and the disruption of these processes is a hallmark of a number of the most prevalent and damaging neuropsychiatric disorders, including depression, addiction, eating disorders, attention deficit hyperactivity disorder, schizophrenia and post-traumatic stress disorder. The experiments outlined in this proposal will greatly expand our knowledge of neural mechanisms controlling associative learning. Elucidating these processes is essential to understanding the pathology of many neuropsychiatric conditions, and these data may help to drive the rationale design of pharmacotherapeutic treatment strategies to ameliorate dysfunction of reward processing, and thus improve treatment outcomes for afflicted individuals.
|Siciliano, Cody A; Saha, Kaustuv; Calipari, Erin S et al. (2018) Amphetamine Reverses Escalated Cocaine Intake via Restoration of Dopamine Transporter Conformation. J Neurosci 38:484-497|
|Vander Weele, Caitlin M; Siciliano, Cody A; Matthews, Gillian A et al. (2018) Dopamine enhances signal-to-noise ratio in cortical-brainstem encoding of aversive stimuli. Nature 563:397-401|
|Siciliano, Cody A; Karkhanis, Anushree N; Holleran, Katherine M et al. (2018) Cross-Species Alterations in Synaptic Dopamine Regulation After Chronic Alcohol Exposure. Handb Exp Pharmacol :|
|Kutlu, Munir Gunes; Brady, Lillian J; Peck, Emily G et al. (2018) Granulocyte Colony Stimulating Factor Enhances Reward Learning through Potentiation of Mesolimbic Dopamine System Function. J Neurosci 38:8845-8859|
|Siciliano, Cody A; McIntosh, J Michael; Jones, Sara R et al. (2017) ?6?2 subunit containing nicotinic acetylcholine receptors exert opposing actions on rapid dopamine signaling in the nucleus accumbens of rats with high-versus low-response to novelty. Neuropharmacology 126:281-291|
|Siciliano, Cody A; Jones, Sara R (2017) Cocaine Potency at the Dopamine Transporter Tracks Discrete Motivational States During Cocaine Self-Administration. Neuropsychopharmacology 42:1893-1904|