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Lateral hypothalamus (LH) neurons containing the neuropeptide hypocretin (HCRT; orexin) modulate affective components of arousal, but their relevant synaptic inputs remain poorly defined. Here we identified inputs onto LH neurons that originate from neuronal populations in the bed nuclei of stria terminalis (BNST; a heterogeneous region of extended amygdala). We characterized two non-overlapping LH-projecting GABAergic BNST subpopulations that express distinct neuropeptides (corticotropin-releasing factor, CRF, and cholecystokinin, CCK). To functionally interrogate BNST→LH circuitry, we used tools for monitoring and manipulating neural activity with cell-type-specific resolution in freely behaving mice. We found that Crf-BNST and Cck-BNST neurons respectively provide abundant and sparse inputs onto Hcrt-LH neurons, display discrete physiological responses to salient stimuli, drive opposite emotionally valenced behaviors, and receive different proportions of inputs from upstream networks. Together, our data provide an advanced model for how parallel BNST→LH pathways promote divergent emotional states via connectivity patterns of genetically defined, circuit-specific neuronal subpopulations.

The gustatory system plays a critical role in sensing appetitive and aversive taste stimuli for evaluating food quality. Although taste preference is known to change depending on internal states such as hunger, a mechanistic insight remains unclear. Here, we examine the neuronal mechanisms regulating hunger-induced taste modification. Starved mice exhibit an increased preference for sweetness and tolerance for aversive taste. This hunger-induced taste modification is recapitulated by selective activation of orexigenic Agouti-related peptide (AgRP)-expressing neurons in the hypothalamus projecting to the lateral hypothalamus, but not to other regions. Glutamatergic, but not GABAergic, neurons in the lateral hypothalamus function as downstream neurons of AgRP neurons. Importantly, these neurons play a key role in modulating preferences for both appetitive and aversive tastes by using distinct pathways projecting to the lateral septum or the lateral habenula, respectively. Our results suggest that these hypothalamic circuits would be important for optimizing feeding behavior under fasting. Hunger modulates perception of good and bad tastes. Here, the authors report that orexigenic AgRP neurons in the hypothalamus mediate these effects through glutamatergic lateral hypothalamic neurons that send distinct projections to the lateral septum and lateral habenula.

Stuber and Wise review the role of the lateral hypothalamic area (LHA) in generating motivated behaviors related to feeding and reward processing. Classic experiments demonstrate that the LHA is critical for reward processing, and more contemporary approaches are beginning to elucidate the cells types and circuits required for these behaviors. In experiments conducted over 60 years ago, the lateral hypothalamic area (LHA) was identified as a critical neuroanatomical substrate for motivated behavior. Electrical stimulation of the LHA induces voracious feeding even in well-fed animals. In the absence of food, animals will work tirelessly, often lever-pressing thousands of times per hour, for electrical stimulation at the same site that provokes feeding, drinking and other species-typical motivated behaviors. Here we review the classic findings from electrical stimulation studies and integrate them with more recent work that has used contemporary circuit-based approaches to study the LHA. We identify specific anatomically and molecularly defined LHA elements that integrate diverse information arising from cortical, extended amygdala and basal forebrain networks to ultimately generate a highly specified and invigorated behavioral state conveyed via LHA projections to downstream reward and feeding-specific circuits.

Nucleus accumbens (NAc) is involved in behaviors that depend on heightened wakefulness, but its impact on arousal remains unclear. Here, we demonstrate that NAc dopamine D receptor (D R)-expressing neurons are essential for behavioral arousal. Using in vivo fiber photometry in mice, we find arousal-dependent increases in population activity of NAc D R neurons. Optogenetic activation of NAc D R neurons induces immediate transitions from non-rapid eye movement sleep to wakefulness, and chemogenetic stimulation prolongs arousal, with decreased food intake. Patch-clamp, tracing, immunohistochemistry, and electron microscopy reveal that NAc D R neurons project to the midbrain and lateral hypothalamus, and might disinhibit midbrain dopamine neurons and lateral hypothalamus orexin neurons. Photoactivation of terminals in the midbrain and lateral hypothalamus is sufficient to induce wakefulness. Silencing of NAc D R neurons suppresses arousal, with increased nest-building behaviors. Collectively, our data indicate that NAc D R neuron circuits are essential for the induction and maintenance of wakefulness.

Pain and anxiety comorbidities are a common health problem, but the neural mechanisms underlying comorbidity remain unclear. We propose that comorbidity implies that similar brain regions and neural circuits, with the lateral septum (LS) as a major candidate, process pain and anxiety. From results of behavioral and neurophysiological experiments combined with selective LS manipulation in mice, we find that LS GABAergic neurons were critical for both pain and anxiety. Selective activation of LS GABAergic neurons induced hyperalgesia and anxiety-like behaviors. In contrast, selective inhibition of LS GABAergic neurons reduced nocifensive withdrawal responses and anxiety-like behaviors. This was found in two mouse models, one for chronic inflammatory pain (induced by complete Freund’s adjuvant) and one for anxiety (induced by chronic restraint stress). Additionally, using TetTag chemogenetics to functionally mark LS neurons, we found that activation of LS neurons by acute pain stimulation could induce anxiety-like behaviors and vice versa. Furthermore, we show that LS GABAergic projection to the lateral hypothalamus (LH) plays an important role in the regulation of pain and anxiety comorbidities. Our study revealed that LS GABAergic neurons, and especially the LS GABAergic -LH circuit, are a critical to the modulation of pain and anxiety comorbidities.

In adult mammals, the adipocyte-derived hormone leptin acts on the brain to reduce food intake by regulating the activity of neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we report that neural projection pathways from the ARH are permanently disrupted in leptin-deficient ($Lep^{ob}/Lep^{ob}$) mice and leptin treatment in adulthood does not reverse these neuroanatomical defects. However, treatment of$Lep^{ob}/Lep^{ob}$neonates with exogenous leptin rescues the development of ARH projections, and leptin promotes neurite outgrowth from ARH neurons in vitro. These results suggest that leptin plays a neurotrophic role during the development of the hypothalamus and that this activity is restricted to a neonatal critical period that precedes leptin's acute regulation of food intake in adults.

Encoding and predicting aversive events are critical functions of circuits that support survival and emotional well-being. Maladaptive circuit changes in emotional valence processing can underlie the pathophysiology of affective disorders. The lateral habenula (LHb) has been linked to aversion and mood regulation through modulation of the dopamine and serotonin systems. We have defined the identity and function of glutamatergic (Vglut2) control of the LHb, comparing the role of inputs originating in the globus pallidus internal segment (GPi), and lateral hypothalamic area (LHA), respectively. We found that LHb-projecting LHA neurons, and not the proposed GABA/glutamate co-releasing GPi neurons, are responsible for encoding negative value. Monosynaptic rabies tracing of the presynaptic organization revealed a predominantly limbic input onto LHA Vglut2 neurons, while sensorimotor inputs were more prominent onto GABA/glutamate co-releasing GPi neurons. We further recorded the activity of LHA Vglut2 neurons, by imaging calcium dynamics in response to appetitive versus aversive events in conditioning paradigms. LHA Vglut2 neurons formed activity clusters representing distinct reward or aversion signals, including a population that responded to mild foot shocks and predicted aversive events. We found that the LHb-projecting LHA Vglut2 neurons encode negative valence and rapidly develop a prediction signal for negative events. These findings establish the glutamatergic LHA-LHb circuit as a critical node in value processing.

Identification of sleep-active and sleep-promoting neurons in the preoptic area of the hypothalamus using neural projection tracing tools to target this population among a group of intermingled neurons, all with various functions. Sleep-promoting neurons in the preoptic area The preoptic area (POA) in the hypothalamus is an essential contributor to typical sleep regulation, but how this brain area is involved in this process has not been well-understood. Now, Yang Dan and colleagues dissect the role of sleep-active neurons in the POA using neural-projection-tracing tools to specifically target this population of neurons amongst a group of intermingled neurons with various functions. The POA sleep neurons were GABAergic and projected to the tuberomammillary nucleus and were not only active during sleep but could promote sleep when activated. Further, single-cell molecular analysis provided candidate genetic markers with which to target these neurons for future studies aiming to further dissect this sleep control circuit. In humans and other mammalian species, lesions in the preoptic area of the hypothalamus cause profound sleep impairment 1 , 2 , 3 , 4 , 5 , indicating a crucial role of the preoptic area in sleep generation. However, the underlying circuit mechanism remains poorly understood. Electrophysiological recordings and c-Fos immunohistochemistry have shown the existence of sleep-active neurons in the preoptic area, especially in the ventrolateral preoptic area and median preoptic nucleus 6 , 7 , 8 , 9 . Pharmacogenetic activation of c-Fos-labelled sleep-active neurons has been shown to induce sleep 10 . However, the sleep-active neurons are spatially intermingled with wake-active neurons 6 , 7 , making it difficult to target the sleep neurons specifically for circuit analysis. Here we identify a population of preoptic area sleep neurons on the basis of their projection target and discover their molecular markers. Using a lentivirus expressing channelrhodopsin-2 or a light-activated chloride channel for retrograde labelling, bidirectional optogenetic manipulation, and optrode recording, we show that the preoptic area GABAergic neurons projecting to the tuberomammillary nucleus are both sleep active and sleep promoting. Furthermore, translating ribosome affinity purification and single-cell RNA sequencing identify candidate markers for these neurons, and optogenetic and pharmacogenetic manipulations demonstrate that several peptide markers (cholecystokinin, corticotropin-releasing hormone, and tachykinin 1) label sleep-promoting neurons. Together, these findings provide easy genetic access to sleep-promoting preoptic area neurons and a valuable entry point for dissecting the sleep control circuit.

Sequential encoding of motor programs is essential for behavior generation. However, whether it is critical for instinctive behavior is still largely unknown. Mouse hunting behavior typically contains a sequential motor program, including the prey search, chase, attack, and consumption. Here, we reveal that the neuronal activity in the lateral periaqueductal gray (LPAG) follows a sequential pattern and is time-locked to different hunting actions. Optrode recordings and photoinhibition demonstrate that LPAG Vgat neurons are required for the prey detection, chase and attack, while LPAG Vglut2 neurons are selectively required for the attack. Ablation of inputs that could trigger hunting, including the central amygdala, the lateral hypothalamus, and the zona incerta, interrupts the activity sequence pattern and substantially impairs hunting actions. Therefore, our findings reveal that periaqueductal gray neuronal ensembles encode the sequential hunting motor program, which might provide a framework for decoding complex instinctive behaviors. Hunting behavior typically contains a sequential motor program, including search, chase, attack, and consumption. Here, the authors show that periaqueductal gray neuronal ensembles encode the sequential hunting motor program, which might provide a framework for decoding complex instinctive behaviors.

Impaired regulation of food intake underlies numerous health problems, including obesity and type 2 diabetes, yet how brain systems controlling reward seeking become dysregulated to promote overeating is unknown. Glutamatergic neurons of the lateral hypothalamic area (LHA) are thought to act as a brake on feeding, which is dysregulated during diet-induced obesity. These neurons receive input from the extended amygdala, including the bed nucleus of the stria terminalis (BNST). However, the circuit mechanisms underlying the ability of this pathway to control feeding behavior and how they contribute to dysregulated eating are unclear. Here, we discover that BNST projections to LHA (BNST→LHA) promote reward seeking in an energy state-dependent manner by combining optogenetics, in vivo multiphoton calcium imaging, and electrophysiology in mice. Synaptic strength and neuronal function within the BNST→LHA pathway are dynamically regulated according to energy state to guide reward seeking. These findings suggest that hormonal factors modulate the function of the BNST→LHA pathway to align food seeking with current energy needs. The lateral hypothalamic area (LHA) mediates reward seeking. Here, the authors show how LHA afferent connections promote reward seeking by shaping synaptic strength according to energy state, processes disrupted by overconsuming palatable food.