Lateral hypothalamic LEPR neurons drive appetitive but not consummatory behaviors.

Assigning behavioral roles to genetically defined neurons within the lateral hypothalamus (LH) is an ongoing challenge. We demonstrate that a subpopulation of LH GABAergic neurons expressing leptin receptors (LHLEPR) specifically drives appetitive behaviors in mice. Ablation of LH GABAergic neurons (LHVGAT) decreases weight gain and food intake, whereas LHLEPR ablation does not. Appetitive learning in a Pavlovian conditioning paradigm is delayed in LHVGAT-ablated mice but prevented entirely in LHLEPR-ablated mice. Both LHVGAT and LHLEPR neurons bidirectionally modulate reward-related behaviors, but only LHVGAT neurons affect feeding. In the Pavlovian paradigm, only LHLEPR activity discriminates between conditioned cues. Optogenetic activation or inhibition of either population in this task disrupts discrimination. However, manipulations of LHLEPR→VTA projections evoke divergent effects on responding. Unlike food-oriented learning, chemogenetic inhibition of LHLEPR neurons does not alter cocaine-conditioned place preference but attenuates cocaine sensitization. Thus, LHLEPR neurons may specifically regulate appetitive behaviors toward non-drug reinforcers.

An excitatory lateral hypothalamic circuit orchestrating pain behaviors in mice.

Understanding how neuronal circuits control nociceptive processing will advance the search for novel analgesics. We use functional imaging to demonstrate that lateral hypothalamic parvalbumin-positive (LHPV) glutamatergic neurons respond to acute thermal stimuli and a persistent inflammatory irritant. Moreover, their chemogenetic modulation alters both pain-related behavioral adaptations and the unpleasantness of a noxious stimulus. In two models of persistent pain, optogenetic activation of LHPV neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LHPV neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LHPV projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LHPV activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LHPV neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.

The neurobiology of wellness: 1H-MRS correlates of agency, flexibility and neuroaffective reserves in healthy young adults.

Proton magnetic resonance spectroscopy (1H-MRS) is a noninvasive imaging technique that measures the concentration of metabolites in defined areas of the human brain in vivo. The underlying structure of natural metabolism-emotion relationships is unknown. Further, there is a wide range of between-person differences in metabolite concentration in healthy individuals, but the significance of this variation for understanding emotion in healthy humans is unclear. Here we investigated the relationship of two emotional constructs, agency and flexibility, with the metabolites glutamate and glutamine (Glx), N-acetylaspartate (tNAA), choline (Cho), creatine (tCr), and myo-inositol (Ins) in the right dorsal anterior cingulate cortex (dACC) in medically and psychiatrically healthy volunteers (N = 20, 9 female; mean age = 22.8 years, SD = 3.40). The dACC was selected because this region is an integrative hub involved in multiple brain networks of emotion, cognition and behavior. Emotional traits were assessed using the Multidimensional Personality Questionnaire Brief Form (MPQ-BF), an empirically derived self-report instrument with an orthogonal factor structure. Phenotypes evaluated were positive and negative agency (MPQ-BF Social Potency, Aggression), emotional and behavioral flexibility (MPQ-BF Absorption, Control-reversed), and positive and negative affect (MPQ-BF Social Closeness; Stress Reaction, Alienation). The resting concentration of tNAA in the dACC was robustly positively correlated with Absorption (r = +0.56, unadjusted p = .005), moderately positively correlated with Social Potency (r = +0.42, unadjusted p = .03), and robustly negatively correlated with Aggression (r = -0.59, unadjusted p = .003). Absorption and Aggression accounted for substantial variance in tNAA (R2 = 0.31, 0.35; combined R2 = 0.50), and survived correction for multiple comparisons (Holm-Bonferroni adjusted p = .032, 0.021, respectively). dACC Glx and Cho had modest relationships with behavioral flexibility and social affiliation that did not survive this multiple correction, providing effect sizes for future work. Principal Component Analysis (PCA) revealed a three-factor orthogonal solution indicating specific relationships between: 1) Glx and behavioral engagement; 2) Cho and affiliative bonding; and 3) tNAA and a novel dimension that we term neuroaffective reserves. Our results inform the neurobiology of agency and flexibility and lay the groundwork for understanding mechanisms of natural emotion using 1H-MRS.

Lateral hypothalamic fast-spiking parvalbumin neurons modulate nociception through connections in the periaqueductal gray area.

A pivotal role of the lateral hypothalamus (LH) in regulating appetitive and reward-related behaviors has been evident for decades. However, the contributions of LH circuits to other survival behaviors have been less explored. Here we examine how lateral hypothalamic neurons that express the calcium-binding protein parvalbumin (PVALB; LHPV neurons), a small cluster of neurons within the LH glutamatergic circuitry, modulate nociception in mice. We find that photostimulation of LHPV neurons suppresses nociception to an acute, noxious thermal stimulus, whereas photoinhibition potentiates thermal nociception. Moreover, we demonstrate that LHPV axons form functional excitatory synapses on neurons in the ventrolateral periaqueductal gray (vlPAG), and photostimulation of these axons mediates antinociception to both thermal and chemical visceral noxious stimuli. Interestingly, this antinociceptive effect appears to occur independently of opioidergic mechanisms, as antagonism of µ-opioid receptors with systemically-administered naltrexone does not abolish the antinociception evoked by activation of this LHPV→vlPAG pathway. This study directly implicates LHPV neurons in modulating nociception, thus expanding the repertoire of survival behaviors regulated by LH circuits.

Activation of a lateral hypothalamic-ventral tegmental circuit gates motivation.

Across species, motivated states such as food-seeking and consumption are essential for survival. The lateral hypothalamus (LH) is known to play a fundamental role in regulating feeding and reward-related behaviors. However, the contributions of neuronal subpopulations in the LH have not been thoroughly identified. Here we examine how lateral hypothalamic leptin receptor-expressing (LHLEPR) neurons, a subset of GABAergic cells, regulate motivation in mice. We find that LHLEPR neuronal activation significantly increases progressive ratio (PR) performance, while inhibition decreases responding. Moreover, we mapped LHLEPR axonal projections and demonstrated that they target the ventral tegmental area (VTA), form functional inhibitory synapses with non-dopaminergic VTA neurons, and their activation promotes motivation for food. Finally, we find that LHLEPR neurons also regulate motivation to obtain water, suggesting that they may play a generalized role in motivation. Together, these results identify LHLEPR neurons as modulators within a hypothalamic-ventral tegmental circuit that gates motivation.