Role of hypothalamic MCH neurons in associative learning and innate exploratory behavior
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2023
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Doctoral Thesis
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yes
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Abstract
The hypothalamus is an ancient structure at the base of the brain which has been long known to control fundamental homeostatic processes such as energy and osmolyte balance, blood pressure and body temperature. Its neurons and transmitters were thought to act on a slow timescale and were often equated to the mode of action of hormones. Today, however, it has become clear that hypothalamic neurons integrate interoception-based homeostatic responses with external stimuli to yield flexible, complex, and rapidly adapting behavioral responses on a fast timescale as well. Additionally, hypothalamic neurons are broadly interconnected with the rest of the brain and participate in a wide variety of functions.
This doctoral work focuses on one hypothalamic population, MCH neurons, which was first identified as a regulator of feeding and sleep but has been more recently found to be an important regulator of cognitive and learning-related processes as well. Although it is known that these neurons are involved in the memorization of novel objects and food-related cues, their involvement in other forms of learning and in innate learning-related behaviors remains unknown.
Here, we use a combination of current and novel tools in systems neuroscience to investigate the relationship between MCH neuron activity and behavior. We find that MCH neurons are responsible for the correct updating of memories after traumatic events, as they are active during aversive experience and disrupting this activity leads to chronic, relapsing, maladaptive fear responses reminiscent of the hallmark symptoms of post-traumatic stress disorder. This finding may provide new therapeutic insights and targets for the treatment of this psychiatric disorder. We also find that MCH neurons drive active information-seeking behavior, known to be important for learning, as they are active during exploratory rearing and exogenous modulation of this activity alters rearing behavior bidirectionally. Furthermore, we identify an inhibitory circuit from stress-related noradrenergic neurons in the locus coeruleus to MCH neurons which gates exploration. These findings provide insights into deep-brain circuits involved in active information-seeking and in its inhibition by stress, with a potential for improvement in the treatment of stress-related disorders.
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ETH Zurich
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09589 - Burdakov, Denis / Burdakov, Denis