Activation of a hypothalamus-habenula circuit by mechanical stimulation inhibits cocaine addiction-like behaviors

BACKGROUND: Mechanoreceptor activation modulates GABA neuron firing and dopamine (DA) release in the mesolimbic DA system, an area implicated in reward and substance abuse. The lateral habenula (LHb), the lateral hypothalamus (LH), and the mesolimbic DA system are not only reciprocally connected, but also involved in drug reward. We explored the effects of mechanical stimulation (MS) on cocaine addiction-like behaviors and the role of the LH-LHb circuit in the MS effects. MS was performed over ulnar nerve and the effects were evaluated by using drug seeking behaviors, optogenetics, chemogenetics, electrophysiology and immunohistochemistry. RESULTS: Mechanical stimulation attenuated locomotor activity in a nerve-dependent manner and 50-kHz ultrasonic vocalizations (USVs) and DA release in nucleus accumbens (NAc) following cocaine injection. The MS effects were ablated by electrolytic lesion or optogenetic inhibition of LHb. Optogenetic activation of LHb suppressed cocaine-enhanced 50 kHz USVs and locomotion. MS reversed cocaine suppression of neuronal activity of LHb. MS also inhibited cocaine-primed reinstatement of drug-seeking behavior, which was blocked by chemogenetic inhibition of an LH-LHb circuit. CONCLUSION: These findings suggest that peripheral mechanical stimulation activates LH-LHb pathways to attenuate cocaine-induced psychomotor responses and seeking behaviors.

Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Modulate the Anesthetic Potency of Isoflurane in Mice / 神经科学通报·英文版

The lateral hypothalamic area (LHA) plays a pivotal role in regulating consciousness transition, in which orexinergic neurons, GABAergic neurons, and melanin-concentrating hormone neurons are involved. Glutamatergic neurons have a large population in the LHA, but their anesthesia-related effect has not been explored. Here, we found that genetic ablation of LHA glutamatergic neurons shortened the induction time and prolonged the recovery time of isoflurane anesthesia in mice. In contrast, chemogenetic activation of LHA glutamatergic neurons increased the time to anesthesia and decreased the time to recovery. Optogenetic activation of LHA glutamatergic neurons during the maintenance of anesthesia reduced the burst suppression pattern of the electroencephalogram (EEG) and shifted EEG features to an arousal pattern. Photostimulation of LHA glutamatergic projections to the lateral habenula (LHb) also facilitated the emergence from anesthesia and the transition of anesthesia depth to a lighter level. Collectively, LHA glutamatergic neurons and their projections to the LHb regulate anesthetic potency and EEG features.

Sex difference in aversive stimulation is associated with the activity of lateral habenula in mice / 西安交通大学学报(医学版)

Objective: To explore the difference in response to aversive stimulation and the expression of CaMK-2β in the lateral habenula between male and female mice. Methods: Male and female mice were given the non-condition stimulation with electric shock associated with the condition-stimulation with the light and tone context. After 24 hours, the mice were placed into the stimulation context and their responses were recorded and analyzed. At 48 hours after non-condition stimulation, the effects on extinction were observed in the male and female mice. Immunohistochemical method was used to detect the number of CaMK-2β positive cells in the lateral habenula nucleus. The expression of CaMK-2β protein in the lateral habenula was detected by Western blot. Results: Female mice were more sensitive to context cue compared with the male mice. Similarly, the female mice were more tolerant to extinction than their male counterparts. Consistently, at 48 hours after aversive stimulation, the CaMK-2β-positive cells in lateral habenula of female mice outnumbered those of the male mice. Additionally, the expression of CaMK-2β in habenula protein was higher in the female mice than in the male mice after aversive stimulation. Conclusion: Male and female mice showed different responses to the same stress stimulation, which determined the consolidation to stress information. The sex difference in aversive stimulation may contribute to the expression of CaMK-2β in the lateral habenula.

Progress on functions of lateral habenula and related mechanisms / 中国药理学通报

Lateral habenula ( LHb ) , which is situated in the dorsal diencephalon of all vertebrates, is an important component of the habenular complex. The neural network outlined in previ-ous studies indicates that LHb acts not only as an important relay station to link the forebrain with the midbrain regions that in-volved in regulating behavioral responses to reward and mediating the transmassion of negative feedback information, but also is closely connected with 5-HT system. Indeed, recently studies demonstrate that experimental manipulations of LHb are followed by behavioural alterations in relation to drug addiction, reward-a-version responses, pain, sleep, depression and so on. This arti-cle mainly reviews the mechanisms of LHb involved in all kinds of physiological activities.