Hypothalamic Circuits In The Control Of Feeding And Emotional Behaviors

Author

Leandra Mangieri, The University of Texas M D Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesFollow

Author ORCID Identifier

0000-0001-8981-0103

Date of Graduation

12-2018

Document Type

Dissertation (PhD)

Program Affiliation

Neuroscience

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Qingchun Tong

Committee Member

Andrew Bean

Committee Member

Vihang Narkar

Committee Member

Michael Beierlein

Committee Member

Benjamin Arenkiel

Abstract

Feeding results from the integration of both nutritional and affective states, and is guided by complex neural circuitry in the brain. The hypothalamus is a critical center controlling feeding and motivated behaviors. We found that targeted photostimulation of projections from the lateral hypothalamus (LH) to the paraventricular hypothalamus (PVH) in mice elicited voracious feeding and repetitive self-grooming behavior. GABA neurotransmission in the LH->PVH circuit mediated the evoked feeding behavior, and elicited behavioral approach, whereas glutamate release promoted repetitive self-grooming, which was stress-related in nature. Optogenetic inhibition of LH^GABA ->PVH circuit reduced feeding after fasting, whereas photostimulation abruptly stopped ongoing self-grooming and immediately elicited feeding. Oppositely, optogenetic inhibition of LH^Glutamate->PVH circuit reduced repetitive self-grooming, whereas photostimulation suppressed fast-refeeding in exchange for repetitive self-grooming. Optogenetically activating and silencing PVH neurons directly recapitulated these findings, and demonstrated the necessity of glutamatergic PVH neurons in mediating the competition between self-grooming and feeding. Together, these results provided evidence that the mutually exclusive nature of feeding and self-grooming behaviors are in part mediated by distinct components in the LH->PVH circuit. Interestingly, photostimulating PVH neurons with greater intensity promoted transitions from grooming to frantic escape-jumping, suggesting scalability of stress-related behaviors mediated by PVH neural activity. Because evoked jumping resembled attempts to escape, we posited PVH neurons mediate defensive responses. Validating this, photostimulating PVH neurons induced avoidance and increased locomotion, two classic behavioral indicators of active defense strategies. Anterograde tracing showed that PVH neurons densely projected to the midbrain region in and surrounding the ventral tegmental area (VTA), a brain region well-known for its roles in motivated behaviors. Indeed, photostimulation of PVH->midbrain projections produced escape behaviors and conditioned place aversion. Combined optogenetic and chemogenetic experiments showed that glutamatergic-midbrain neurons were required for escape behaviors. Further, glutamatergic-midbrain neurons displayed increased neural population activity in vivo during a fear-provoking situation, validating a role for this population in processing threat. Taken together, our work reveals novel hypothalamic circuits in the control of feeding, emotional valence, and behaviors related to stress and defense. These findings shed light on possible neural mechanisms underlying complex disease states characterized by feeding abnormalities, anxiety and fear.

Keywords

hypothalamus, feeding, emotion, midbrain, ventral tegmental area, grooming, fear, escape, optogenetics, mouse model