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.

Three-Dimensional Analysis of Mouse Habenula Subnuclei Reveals Reduced Volume and Gene Expression in the Lipopolysaccharide-mediated Depression Model

The habenula (Hb) is small but important brain structure, anatomically and functionally links the forebrain with the midbrain to modulate various neuropsychiatric functions associated with drug addiction and emotion-associated dysfunctions. Several reports suggested that the dysfunction of Hb-related functions affected the Hb structurally and functionally. However, the technical limitation has awaited the solid conclusion of whether Hb change due to depression is likely to occur in certain subnuclei of the Hb. To probe this possibility, we developed 3-dimensional reconstruction methods for the high-resolution volumetric analysis of Hb and the mRNA levels at the given volume in normal or lipopolysaccharide (LPS)-mediated mouse model of depression. Notably, we discovered that the volume reduction was prominent in medial Hb but not in lateral Hb after LPS treatments. On the other hand, the RNA expression levels of known Hb regional markers such as Tac1 (dorsal part of medial Hb), ChAT (ventral part of medial Hb), and Tacr1 (medial and lateral Hb) were all decreased in all Hb subnuclei in LPS-injected mice. Accordingly, accurate volumetry with marker labeling was not feasible. Collectively, these established 3D analyses of mouse Hb successfully and precisely determine the volume-based changes of small brain structure, which should be applicable in a wider range of mouse models or pathological specimens.

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.

Efectos de la estimulación eléctrica habenular en la modulación de respuestas emocionales en ratas Wistar / Efeitos da estimulação elétrica habenular na modulação de respostas emocionais em ratos Wistar / Effects of electrical stimulation of the habenula on the modulation of emotional responses in Wistar rats

Resumen A pesar del amplio uso de la estimulación cerebral profunda para controlar patologías neurológicas y neuropsiquiátricas, su mecanismo de acción aún no es claramente conocido, y existen pocos estudios sistemáticos que relacionen la variación de parámetros de estimulación eléctrica (frecuencia, intensidad, duración del pulso) y la ejecución comportamental. La habénula es una estructura reguladora de respuestas emocionales diana en tratamientos para dolor crónico y depresión, pero la relación entre su estimulación crónica y el desempeño animal en pruebas conductuales no se ha establecido con claridad. Con el objetivo de evaluar el efecto emocional de la estimulación habenular crónica, en este estudio se utilizaron ratas Wistar que recibieron estimulación habenular a intensidad baja (10-80 pA) o alta (120-260 pA) y frecuencia baja (80-150 Hz) o alta (240380 Hz): BIBF-AIBF-BIAF-AIAF, durante 15 minutos a lo largo de tres días consecutivos. Al cuarto día, se hizo la evaluación en un laberinto elevado en cruz y en campo abierto. Los resultados indican un efecto de tipo ansiolítico en el tratamiento BIAF, en comparación con BIBF y AIBF (aumento del número de entradas, porcentaje de tiempo en brazos abiertos y de la distancia recorrida en ellos), efecto que no se explica por cambios en la locomotricidad (distancia recorrida en los brazos cerrados y la exploración en el campo abierto). Se concluye que el parámetro frecuencia posee mayor impacto sobre el efecto comportamental que la intensidad -lo que puede explicar algunos hallazgos paradójicos previos-, que los parámetros utilizados no poseen efecto ansiogénico, y que los efectos potencialmente ansiogénicos de la estimulación a baja frecuencia y el papel de los sistemas dopaminérgicos y serotoninérgicos encontrados deben ser estudiados en futuras investigaciones.

Resumo Apesar do amplo uso da estimulação cerebral profunda para controlar patologias neurológicas e neuropsiquiátricas, seu mecanismo de ação ainda não é claramente conhecido e existem poucos estudos sistemáticos que relacionem a variação de parâmetros de estimulação elétrica (frequência, intensidade, duração do pulso) e a execução comportamental. A habênula é uma estrutura reguladora de respostas emocionais específicas em tratamentos para dor crònica e depressão, mas a relação entre sua estimulação crònica e o desempenho animal em testes comportamentais não foi claramente estabelecida. Com o objetivo de avaliar o efeito emocional da estimulação habenular crònica, neste estudo foram utilizados ratos Wistar que receberam estimulação habenular de intensidade baixa (10-80 pA) ou alta (120-260 pA) e frequência baixa (80-150 Hz) ou alta (240-380 Hz): BIBF-AIBF-BIAF-AIAF, durante 15 minutos ao longo de três dias consecutivos. No quarto dia, foi feita a avaliação em um labirinto em cruz elevado e em campo aberto. Os resultados indicam um efeito de tipo ansiolítico no tratamento BIAF, em comparação com BIBF e AIBF (aumento do número de entradas, porcentagem de tempo em braços abertos e da distância percorrida neles), efeito que não se explica por mudanças na locomotividade (distância percorrida nos braços fechados e a exploração no campo aberto). Conclui-se que o parâmetro "frequência" tem mais impacto sobre o efeito comportamental do que a "intensidade" - o que pode explicar algumas descobertas paradoxais prévias -, que os parâmetros utilizados não tenham efeito ansiogênico, e que os efeitos potencialmente ansiogênicos da estimulação de baixa frequência e o papel dos sistemas dopaminérgicos e serotoninérgicos encontrados devem ser estudados em pesquisas futuras.

Abstract Deep brain stimulation is a widely-used approach to the treatment of neurologic and neuropsychiatric diseases. However, its mechanisms remain unclear. There are few systematic studies relating variations on electrical stimulation parameters (frequency, intensity, pulse duration) and behavioral outcome. The habenula relates to emotional behavior and is a main target for chronic pain and depression stimulation treatment. The relation between habenular electrical stimulation and performance in behavioral tests has not been clearly defined. In order to assess the emotional effects of chronic habenular electrical stimulation, Wistar male rats were unilaterally implanted with electrodes aimed to the lateral habenula and assigned to low (10-80 pA) or high (120-260 pA) intensity and low (80-150 Hz) or high (240-380 Hz) frequency conditions: BIBF-AIBF-BIAF-AIAF. They received electrical stimulation 15 minutes/day for three consecutive days and on the fourth day were tested in the elevated plus maze and the open field. The results of these study show that BIAF stimulation has a possible anxiolytic-like effect when compared to BIBF and AIBF (increase in the percentage of open-arms time, entries into the open-arms and total-distance-run in the open-arms). This is not due to any changes in locomotion (total-distance-run and open field exploration). It is concluded that frequency is more important than intensity for behavioral modification. This could explain some previous inconsistent results. The data also suggest that these parameters of stimulation have no anxiogenic effects. The role for dopaminergic and serotonergic systems must be subsequently evaluated as well as potential anxiogenic-like effects of low frequency stimulation.

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.

Advances of mechanism of habenula in reward and its role in mental illness / 中国药理学与毒理学杂志

The habenula complex,an ancient and conservative nucleus during biological evolution, is involved in many i mportant biological functions,such as maternal behavior,pain,sleep,learning and reward.As an important node in the dopamine reward network,its functions(including the maintenance of individual survival while avoiding disadvantages)and mechanis m in the reward process have attracted wide attention.The dysfunction of habenula is closely related to many psychotic disorders,such as de-pression,schizophrenia and drug habituation.Habenula may also become a potential target for clinical treatment of these mental illnesses.So clarifying the role and neurobiological mechanisms of habenula in the central nervous system is of great theoretical and clinical value.

The effects of adenosine on the discharging electricities and the c-fos expression of neurons in habenula nucleus of rats / 中国免疫学杂志

Objective:To investigate the effect of adenosine (Ado) on the unit discharging electricities in habenula nucleus and on the c-fos expression in lateral habenular complex,and the influence of adenosine on the neuron activities and related gene expression involved in affecting sleep in habenula nucleus and the possible mechanisms.Methods:Intraperitoneal injection,brain flakes pouring of rats,immunohistochemistry and other methods were useel.Results:Ado pouring into flakes of brain depressed the unit discharging electricities of neurons in medial habenular complex(MHb),but obviously increased that of lateral habenular complex(LHb).0.5 h after the six rats being injected intraperitoneally with Ado,the c-fos protein expression in lateral habenular nucleus was significantly increased compared to the group with saline injection.Conclusion:Ado may restrain the unit discharging electricities of neurons in medial habenular complex but excite those in lateral habenular complex.At the meantime,Ado may increase the c-fos expression in LHb.This provides the experimental evidence that Ado may improve the sleep quality.