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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.

The lateral hypothalamus (LH) is classically implicated in sleep-wake control. It is the main source of orexin/hypocretin and melanin-concentrating hormone (MCH) neuropeptides in the brain, which have been both implicated in arousal state switching. These neuropeptides are produced by non-overlapping LH neurons, which both project widely throughout the brain, where release of orexin and MCH activates specific postsynaptic G-protein-coupled receptors. Optogenetic manipulations of orexin and MCH neurons during sleep indicate that they promote awakening and REM sleep, respectively. However, recordings from orexin and MCH neurons in awake, moving animals suggest that they also act outside sleep/wake switching. Here, we review recent studies showing that both orexin and MCH neurons can rapidly (sub-second-timescale) change their firing when awake animals experience external stimuli, or during self-paced exploration of objects and places. However, the sensory-behavioral correlates of orexin and MCH neural activation can be quite different. Orexin neurons are generally more dynamic, with about 2/3rds of them activated before and during self-initiated running, and most activated by sensory stimulation across sensory modalities. MCH neurons are activated in a more select manner, for example upon self-paced investigation of novel objects and by certain other novel stimuli. We discuss optogenetic and chemogenetic manipulations of orexin and MCH neurons, which combined with pharmacological blockade of orexin and MCH receptors, imply that these rapid LH dynamics shape fundamental cognitive and motor processes due to orexin and MCH neuropeptide actions in the awake brain. Finally, we contemplate whether the awake control of psychomotor brain functions by orexin and MCH are distinct from their “arousal” effects. ISSN:1662-453X ISSN:1662-4548

The lateral hypothalamus (LH) is classically implicated in sleep-wake control. It is the main source of orexin/hypocretin and melanin-concentrating hormone (MCH) neuropeptides in the brain, which have been both implicated in arousal state switching. These neuropeptides are produced by non-overlapping LH neurons, which both project widely throughout the brain, where release of orexin and MCH activates specific postsynaptic G-protein-coupled receptors. Optogenetic manipulations of orexin and MCH neurons during sleep indicate that they promote awakening and REM sleep, respectively. However, recordings from orexin and MCH neurons in awake, moving animals suggest that they also act outside sleep/wake switching. Here, we review recent studies showing that both orexin and MCH neurons can rapidly (sub-second-timescale) change their firing when awake animals experience external stimuli, or during self-paced exploration of objects and places. However, the sensory-behavioral correlates of orexin and MCH neural activation can be quite different. Orexin neurons are generally more dynamic, with about 2/3rds of them activated before and during self-initiated running, and most activated by sensory stimulation across sensory modalities. MCH neurons are activated in a more select manner, for example upon self-paced investigation of novel objects and by certain other novel stimuli. We discuss optogenetic and chemogenetic manipulations of orexin and MCH neurons, which combined with pharmacological blockade of orexin and MCH receptors, imply that these rapid LH dynamics shape fundamental cognitive and motor processes due to orexin and MCH neuropeptide actions in the awake brain. Finally, we contemplate whether the awake control of psychomotor brain functions by orexin and MCH are distinct from their “arousal” effects., Frontiers in Neuroscience, 15, ISSN:1662-453X, ISSN:1662-4548