Lateral Habenula Neuronal Activity Research Articles

Improving depression-like behaviors caused by diabetes is likely to offer a new perspective for the treatment of non-healing chronic wounds.

Three phases are often involved in the intricate process of wound healing: inflammatory exudation, cell proliferation, and tissue remodeling. It is challenging for wounds to heal if conditions like ischemia, persistent pressure, infection, repetitive trauma, or systemic or localized illnesses arise during the healing process. Chronic wounds are persistent injuries that do not follow the normal healing process and fail to progress through the stages of healing within a reasonable timeframe, like diabetic ulcers, vascular ulcers, pressure sores, and infectious wounds. Various factors affect chronic wound healing. A large body of research has illuminated that psychological distress may often be related to wound healing in clinical settings. Our observations have indicated that the pace of wound healing in diabetic mice is generally slower than that of healthy mice, and mice induced by streptozotocin (STZ) and fed a high-fat diet generally exhibit depression-like behavior. Our experiment delves into whether there is an inherent correlation and provides new ideas for clinical treatment to promote wound healing. In order to explore the relationship between diabetes, depression, and wound healing, we observed wound healing through HE staining, Masson's trichrome staining, and IHC staining for CD31 and detected the depressive condition through behavioral tests. Then, RT-PCR was used to detect the mRNA expression levels of α-SMA, Col1, CD31, and VEGF in wound tissue. Finally, the related brain areas were regulated through chemical genetic methods and the process of wound healing was observed. It has been observed that the lateral habenula (LHb) areas are associated with depression-like behavior induced by diabetes. Inhibiting LHb neuronal activity mitigates these depressive symptoms and enhances wound healing. Refractory wounds can be improved by considering patients' emotional issues from a broad standpoint, which provides fresh concepts for potential clinical treatments in the future.

Dapagliflozin inhibits the activity of lateral habenula to alleviate diabetes mellitus-induced depressive-like behavior

The prevalence of depression in diabetes mellitus (DM) patients is very high, and it severely impacts the prognosis and quality of life of these patients. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, a new type of oral hypoglycemic drugs, have been shown to alleviate depressive symptoms in DM patients; however, the mechanism underlying this effect is not well understood. The lateral habenula (LHb) plays an important role in the pathogenesis of depression expresses SGLT2, suggesting that the LHb may mediate antidepressant effects of SGLT2 inhibitors. The current study aimed to investigate the involvement of the LHb in the antidepressant effects of the SGLT2 inhibitor dapagliflozin. Chemogenetic methods were used to manipulate the activity of LHb neurons. Behavioral tests, Western blotting, immunohistochemistry, and neurotransmitter assays were used to determine the effects of dapagliflozin on the behavior of DM rats, AMP-activated protein kinase (AMPK) pathway and c-Fos expression in the LHb and 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratio in the dorsal raphe nucleus (DRN). We found that DM rats demonstrated depressive-like behavior, increased c-Fos expression, and decreased AMPK pathway activity in the LHb. Inhibition of LHb neurons alleviated the depressive-like behavior of DM rats. Both systemic and local LHb administration of dapagliflozin alleviated the depressive-like behavior and reversed the changes of the AMPK pathway and c-Fos expression in the LHb of DM rats. Dapagliflozin, when microinjected into the LHb, also increased 5-HIAA /5-HT in the DRN. These results suggest that dapagliflozin directly acts on the LHb to alleviate DM-induced depressive-like behavior and that the underlying mechanism involves activating the AMPK signaling pathway, leading to the inhibition of LHb neuronal activity, which in turn increases serotonergic activity in the DRN. These results will help develop new strategies for the treatment of DM-induced depression.

Effects of GABAB receptor blockade on lateral habenula glutamatergic neuron activity following morphine injection in the rat: an electrophysiological study.

The lateral habenula (LHb), a key area in the regulation of the reward system, exerts a major influence on midbrain neurons. It has been shown that the gamma-aminobutyric acid (GABA)- ergic system plays the main role in morphine dependency. The role of GABA type B receptors (GABABRs) in the regulation of LHb neural activity in response to morphine, remains unknown. In this study, the effect of GABABRs blockade in response to morphine was assessed on the neuronal activity in the LHb. The baseline firing rate was recorded for 15 min, then morphine (5 mg/kg; s.c) and phaclofen (0, 0.5, 1, and 2 μg/rat), a GABABRs' antagonist, were microinjected into the LHb. Their effects on firing LHb neurons were investigated using an extracellular single-unit recording in male rats. The results revealed that morphine decreased neuronal activity, and GABABRs blockade alone did not have any effect on the neuronal activity of the LHb. A low dose of the antagonist had no significant effect on neuronal firing rate, while blockade with doses of 1 and 2 μg/rat of the antagonist could significantly prevent the inhibitory effects of morphine on the LHb neuronal activity. This result indicated that GABABRs have a potential modulator effect, in response to morphine in the LHb.

5-HT1B receptor-AC-PKA signal pathway in the lateral habenula is involved in the regulation of depressive-like behaviors in 6-hydroxydopamine-induced Parkinson’s rats

ABSTRACT Objective The aim of the present study was to investigate whether serotonin1B (5-HT1B) receptor-adenylate cyclase (AC)-protein kinase A (PKA) signal pathway in the lateral habenula (LHb) is involved in Parkinson’s disease-related depression in sham-lesioned and substantia nigra pars compacta (SNc)-lesioned rats. Methods The sucrose preference and forced swim tests were used to measure depressive-like behaviors. In vivo electrophysiology and microdialysis were performed to observe the firing activity of LHb neurons and GABA and glutamate release in the LHb, respectively. Western blotting was used to analyze protein expression of 5-HT1B receptors, AC and phosphorylated PKA at threonine 197 site (p-PKA-Thr197) in the LHb. Results Unilateral 6-hydroxydopamine lesions of the SNc in rats induced depressive-like behaviors. Intra-LHb injection of 5-HT1B receptor agonist CP93129 produced antidepressant-like effects and the antagonist SB216641 induced depressive-like behaviors in sham-lesioned and SNc-lesioned rats. Further, pretreatment with AC inhibitor SQ22536 and PKA inhibitor KT5720 blocked the behavioral effects of CP93129 in the two groups of rats, respectively. CP93129 decreased the firing rate of LHb neurons and release of GABA and glutamate, but increased the GABA/glutamate ratio, while SB216641 induced the opposite effects. Compared with sham-lesioned rats, effects of CP93129 and SB216641 on the depressive-like behaviors, electrophysiology, and microdialysis were decreased in SNc-lesioned rats, which were associated with decreased expression of 5-HT1B receptors, AC and p-PKA-Thr197 in the LHb. Conclusion 5-HT1B receptor-AC-PKA signal pathway in the LHb is involved in the regulation of depressive-like behaviors, and depletion of DA reduces activity of 5-HT1B receptor-AC-PKA signal pathway.

Synaptic inhibition in the lateral habenula shapes reward anticipation

The lateral habenula (LHb) supports learning processes enabling the prediction of upcoming rewards. While reward-related stimuli decrease the activity of LHb neurons, whether this anchors on synaptic inhibition to guide reward-driven behaviors remains poorly understood. Here, we combine invivo two-photon calcium imaging with Pavlovian conditioning in mice and report that anticipatory licking emerges along with decreases in cue-evoked calcium signals in individual LHb neurons. Invivo multiunit recordings and pharmacology reveal that the cue-evoked reduction in LHb neuronal firing relies on GABAA-receptor activation. In parallel, we observe a postsynaptic potentiation of GABAA-receptor-mediated inhibition, but not excitation, onto LHb neurons together with the establishment of anticipatory licking. Finally, strengthening or weakening postsynaptic inhibition with optogenetics and GABAA-receptor manipulations enhances or reduces anticipatory licking, respectively. Hence, synaptic inhibition in the LHb shapes reward anticipation.

Lateral habenula neurocircuits mediate the maternal disruptive effect of maternal stress: A hypothesis.

Up to 20% of women experience stress-related disorders during the postpartum period; however, little is known about the specific neural circuitry by which maternal stress exerts its negative impacts on mental health and maternal caregiving behavior. Theoretically, such a circuitry should serve as an interface between the stress response system and maternal neural network, transmitting stress signals to the neural circuitry that mediates maternal behavior. In this paper, I propose that the lateral habenula (LHb) serves this interface function. Evidence shows that the LHb plays a key role in encoding stress-induced effects and in the pathophysiology of major depression and stress-related anxiety, and thus may play a role in maternal behavior as part of the maternal brain network. I hypothesize that maternal stress acts upon the LHb and two of its major downstream targets, i.e., ventral tegmental area (VTA) and dorsal raphe nucleus (DRN), compromising the maternal care and contributing to postpartum mental disorders. This hypothesis makes three predictions: (1) maternal stress enhances LHb neuronal activity; (2) activation of DRN- and VTA-projecting neurons in the LHb mimics the detrimental effects of maternal stress on maternal behavior; and (3) suppression of DRN- and VTA-projecting neurons in the LHb attenuates the detrimental effects of maternal stress on maternal care in stressed mothers. Confirmation of this hypothesis is expected to enhance our understanding of the neurocircuit mechanisms mediating stress effects on maternal behavior.

Input‐specific regulation of discrete populations of Lateral Habenula neurons by Kappa opioid receptors

The lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of reward circuitry. Increased activity of the LHb is associated with drug addiction and stress-related mood disorders. Dynorphin (DYN)/Kappa opioid receptor (KOR) signaling is an endogenous mediator of stress response in reward circuitry. Previously, we have shown a novel functional role of DYN/KOR signaling within LHb and its dysregulation by a severe early life stress (maternal deprivation, MD). Specifically, KOR stimulation has distinct effects on LHb neuronal excitability in distinct neuronal populations identified by the presence of hyperpolarizing current (Ih) that were absent following MD. Namely, KOR stimulation through the KOR agonist, U50,488, significantly decreases excitability of Ih negative (Ih-) LHb neurons while simultaneously increasing excitability of Ih positive (Ih+) LHb neurons. Additionally, KOR-induced alteration in LHb excitability is dependent on both presynaptic glutamatergic and GABAergic signaling likely through presynaptic KORs on inputs to LHb neurons. Given that LHb inputs from the entopeduncular nucleus (EP) and lateral hypothalamus (LH) have been implicated in stress-induced mood disorders through modulation of LHb excitability, we hypothesize that the presynaptic effects of KOR stimulation on LHb neuronal activity may be driven by one or both of these inputs. Using selective in vitro optical stimulation of either EP or LH inputs to LHb neurons in brain slices from rats, our pilot study suggests that KOR activation of EP and LH inputs may differentially affect optically evoked action potential generation across Ih- and Ih+ LHb subpopulations. Moreover, our data from MD rats suggest that there may be an imbalance of excitation to inhibition at EP synapses onto LHb neurons. Given that MD increases immunolabeled DYN (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreasing mRNA levels of KORs in LHb, we also investigated MD-induced modulation of a KOR-specific downstream signaling (p38 MAPK). Our molecular data indicate that decreased KOR expression may be a homeostatic response to higher basal activation of KORs by MD-induced increases in DYN and p38 expression in the LHb. Ih- and Ih+ neurons molecular identification is further investigated following electrophysiological recordings by combining ionophoresis labeling during electrophysiology experiments and post-hoc immunohistochemistry to verify the glutamatergic (VGLUT+) and GABAergic (somatostatin, SST+ or parvalbumin, PV) nature of LHb neurons. Collectively, our current studies provide evidence for input- and cell-specific regulation of LHb neurons by KOR signaling that could be modulated by MD and highlights a future hotspot for pharmacological intervention of KOR-mediated mood disorders through dysregulation of specific LHb neural circuits.

Behavior: Local Lateral Habenula Interneurons Mediate Aggression

A recent study has shown that local inhibitory GAD2-positive neurons regulate the activity of lateral habenula neurons, thereby governing aggressive behavior in male mice.

Heterogeneous Habenular Neuronal Ensembles during Selection of Defensive Behaviors

SummaryOptimal selection of threat-driven defensive behaviors is paramount to an animal’s survival. The lateral habenula (LHb) is a key neuronal hub coordinating behavioral responses to aversive stimuli. Yet, how individual LHb neurons represent defensive behaviors in response to threats remains unknown. Here, we show that in mice, a visual threat promotes distinct defensive behaviors, namely runaway (escape) and action-locking (immobile-like). Fiber photometry of bulk LHb neuronal activity in behaving animals reveals an increase and a decrease in calcium signal time-locked with runaway and action-locking, respectively. Imaging single-cell calcium dynamics across distinct threat-driven behaviors identify independently active LHb neuronal clusters. These clusters participate during specific time epochs of defensive behaviors. Decoding analysis of this neuronal activity reveals that some LHb clusters either predict the upcoming selection of the defensive action or represent the selected action. Thus, heterogeneous neuronal clusters in LHb predict or reflect the selection of distinct threat-driven defensive behaviors.

Kv7.2 subunit-containing M-type potassium channels in the lateral habenula are involved in the regulation of working memory in parkinsonian rats

Although the lateral habenula (LHb) is involved in the regulation of multiple brain functions and this region expresses abundant M-type potassium channel (M-channel) subunits Kv7.2 and Kv7.3, the role of M-channels in regulating working memory is unclear, particularly in Parkinson's disease (PD). Here we tested the effects of activation and blockade of LHb M-channels on working memory by the T-maze rewarded alternation test in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra compacta (SNc). The SNc lesion induced working memory impairment, increased the firing rate of LHb neurons, decreased dopamine (DA) level in the ventral medial prefrontal cortex (vmPFC) and reduced the expression of Kv7.2 subunit in the LHb. Intra-LHb injection of M-channel activator retigabine induced enhancement of working memory in SNc sham-lesioned and SNc-lesioned rats; conversely, the injection of M-channel blocker XE-991 impaired working memory in the two groups of rats. However, doses producing significant effects in SNc-lesioned rats were higher than those in SNc sham-lesioned rats. Further, intra-LHb injection of retigabine decreased the firing rate of LHb neurons and increased release of DA and serotonin (5-HT) in the vmPFC, while XE-991 increased the firing rate and decreased DA and 5-HT release in the two groups of rats. Compared with SNc sham-lesioned rats, the duration of M-channel activation and blockade action on the firing rate of the neurons and release of DA and 5-HT was significantly shortened in SNc-lesioned rats, which was consistent with reduced expression of Kv7.2 subunit in the LHb after lesioning the SNc. Collectively, these findings suggest involvement of LHb Kv7.2 subunit-containing M-channels in working memory impairment in SNc-lesioned rats, and that enhanced or impaired working memory after activation or blockade of M-channels in the LHb is related to the changes in the firing activity of LHb neurons and DA and 5-HT release in the vmPFC.

Blockade of calcium-permeable AMPA receptors in the lateral habenula produces increased antidepressant-like effects in unilateral 6-hydroxydopamine-lesioned rats compared to sham-lesioned rats

At present, role of the lateral habenula (LHb) calcium-permeable AMPA receptors (CP-AMPARs) in depression is not understood, particularly in Parkinson's disease-related depression. Here we found that lesions of the substantia nigra pars compacta (SNc) in rats induced depressive-like behaviors, and intra-LHb injection of CP-AMPAR antagonist Naspm produced antidepressant-like effects in SNc sham-lesioned and SNc-lesioned rats, however, the doses inducing these effects in SNc-lesioned rats were lower than that of SNc sham-lesioned rats. Blockade of LHb CP-AMPARs decreased the firing rate of the neurons and increased release of dopamine and serotonin in the medial prefrontal cortex (mPFC) in both groups, but the duration of Naspm action on the firing rate and release of the transmitters were prolonged in SNc-lesioned rats. These changes in SNc-lesioned rats were involved in increased expression of βCaMKII and p-GluR1-S831 in the LHb. Intra-LHb injection of Naspm inhibited dopaminergic neurons in the anterior ventral tegmental area and serotonergic neurons in the dorsal raphe nucleus and excited dopaminergic neurons in the posterior ventral tegmental area (pVTA) and serotonergic neurons in the median raphe nucleus (MRN), and lesioning the GABAergic rostromedial tegmental nucleus (RMTg) decreased the percentages of excited pVTA dopaminergic neurons and MRN serotonergic neurons. Our findings indicate that blockade of LHb CP-AMPARs produces antidepressant-like effects, which attribute to decreased firing activity of LHb neurons and increased levels of dopamine and serotonin in the mPFC, and provide further evidence that LHb CP-AMPARs regulate the firing activity of pVTA dopaminergic neurons and MRN serotonergic neurons indirectly via the RMTg.

Stress transforms lateral habenula reward responses into punishment signals

Neuronal activity in the lateral habenula (LHb), a brain region implicated in depression [C. D. Proulx, O. Hikosaka, R. Malinow, Nat. Neurosci. 17, 1146-1152 (2014)], decreases during reward and increases during punishment or reward omission [M. Matsumoto, O. Hikosaka, Nature 447, 1111-1115 (2007)]. While stress is a major risk factor for depression and strongly impacts the LHb, its effect on LHb reward signals is unknown. Here we image LHb neuronal activity in behaving mice and find that acute stress transforms LHb reward responses into punishment-like neural signals; punishment-like responses to reward omission also increase. These neural changes matched the onset of anhedonic behavior and were specific to LHb neurons that distinguished reward and its omission. Thus, stress distorts LHb responsivity to positive and negative feedback, which could bias individuals toward negative expectations, a key aspect of the proposed pathogenesis of depression [A. T. Beck, Depression: Clinical, Experimental, and Theoretical Aspects, sixth Ed (1967)].

Elevation of Transient Receptor Potential Vanilloid 1 Function in the Lateral Habenula Mediates Aversive Behaviors in Alcohol-withdrawn Rats.

Chronic alcohol use and withdrawal leads to increased pain perception, anxiety, and depression. These aberrant behaviors are accompanied by increased excitatory glutamatergic transmission to, and activity of, the lateral habenula neurons.Vanilloid type 1, or TRPV1, channels are expressed in the habenula and they facilitate glutamatergic transmission. Whether TRPV1 channel plays a role in habenula hyperactivity is not clear. Glutamatergic transmission in the lateral habenula was inhibited by TRPV1 channel antagonists. In vivo, local administration of TRPV1 antagonists into the lateral habenula attenuated hyperalgesia, anxiety, and relapse-like drinking in rats who chronically consumed alcohol.The data suggest that enhanced TRPV1 channel function during withdrawal may contribute to aberrant behavior that promotes relapse alcohol consumption. Recent rat studies indicate that alcohol withdrawal can trigger a negative emotional state including anxiety- and depression-like behaviors and hyperalgesia, as well as elevated glutamatergic transmission and activity in lateral habenula neurons. TRPV1, a vanilloid receptor expressed in the habenula, is involved in pain, alcohol dependence, and glutamatergic transmission. The authors therefore hypothesized that TRPV1 contributes to the changes in both the behavioral phenotypes and the habenula activity in alcohol-withdrawn rats. Adult male Long-Evans rats (n = 110 and 280 for electrophysiology and behaviors, respectively), randomly assigned into the alcohol and water (Naïve) groups, were trained to consume either alcohol or water-only using an intermittent-access procedure. Slice electrophysiology was used to measure spontaneous excitatory postsynaptic currents and firing of lateral habenula neurons. The primary outcome was the change in alcohol-related behaviors and lateral habenula activity induced by pharmacologic manipulation of TRPV1 activity. The basal frequency of spontaneous excitatory postsynaptic currents and firing of lateral habenula neurons in alcohol-withdrawn rats was significantly increased. The TRPV1 antagonist capsazepine (10 µM) induced a stronger inhibition on spontaneous excitatory postsynaptic currents (mean ± SD; by 26.1 ± 27.9% [n = 11] vs. 6.7 ± 18.6% [n = 17], P = 0.027) and firing (by 23.4 ± 17.6% [n = 9] vs. 11.9 ± 16.3% [n = 12], P = 0.025) in Withdrawn rats than Naive rats. By contrast, the TRPV1 agonist capsaicin (3 μM) produced a weaker potentiation in Withdrawn than Naïve rats (spontaneous excitatory postsynaptic currents: by 203.6 ± 124.7% [n = 20] vs. 415.2 ± 424.3% [n = 15], P < 0.001; firing: 38.1 ± 14.7% [n = 11] vs. 73.9 ± 41.9% [n = 11], P < 0.001). Conversely, capsaicin's actions in Naïve but not in Withdrawn rats were significantly attenuated by the pretreatment of TRPV1 endogenous agonist N-Oleoyldopamine. In Withdrawn rats, intra-habenula infusion of TRPV1 antagonists attenuated hyperalgesia and anxiety-like behaviors, decreased alcohol consumption upon resuming drinking, and elicited a conditioned place preference. Enhanced TRPV1 function may contribute to increased glutamatergic transmission and activity of lateral habenula neurons, resulting in the aberrant behaviors during ethanol withdrawal.

Preferential modulation of the lateral habenula activity by serotonin-2A rather than -2C receptors: Electrophysiological and neuroanatomical evidence.

Serotonergic (5-HT) modulation of the lateral habenula (LHb) activity is central in normal and pathologic conditions such as mood disorders. Among the multiple 5-HT receptors (5-HTRs) involved, the 5-HT2C R seems to play a pivotal role. Yet, the role of 5-HT2A Rs in the control of the LHb neuronal activity is completely unknown. Single-cell extracellular recording of the LHb neurons was used in rats to study the effect of the general activation and blockade of the 5-HT2C R and 5-HT2A R with Ro 60-0175 and SB242084, TCB-2 and MDL11939, respectively. The expression of both receptors in the LHb was confirmed using immunohistochemistry. Cumulative doses (5-640μg/kg, iv) of Ro 60-0175 and TCB-2 affected the activity of 34% and 63% of the LHb recorded neurons, respectively. LHb neurons were either inhibited at low doses or excited at higher doses of the 5-HT2A/C R agonists. SB242084 or MDL11939 (both at 200μg/kg, iv) did not modify neuronal firing when injected alone, but reverted the bidirectional effects of Ro 60-0175 or TCB-2, respectively. 5-HT2C Rs and 5-HT2A Rs are expressed in less than the 20% of the LHb neurons, and they neither colocalize nor make heterodimers. Strikingly, only 5-HT2A Rs are expressed by the majority of LHb astrocyte cells. Peripheral administration of 5-HT2A R agonist promotes a heterogeneous pattern of neuronal responses in the LHb, and these effects are more prominent than those induced by the 5-HT2C R activation.

Ketamine blocks bursting in the lateral habenula to rapidly relieve depression.

The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the 'anti-reward center', the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.

Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression.

Enhanced bursting activity of neurons in the lateral habenula (LHb) is essential in driving depression-like behaviours, but the cause of this increase has been unknown. Here, using a high-throughput quantitative proteomic screen, we show that an astroglial potassium channel (Kir4.1) is upregulated in the LHb in rat models of depression. Kir4.1 in the LHb shows a distinct pattern of expression on astrocytic membrane processes that wrap tightly around the neuronal soma. Electrophysiology and modelling data show that the level of Kir4.1 on astrocytes tightly regulates the degree of membrane hyperpolarization and the amount of bursting activity of LHb neurons. Astrocyte-specific gain and loss of Kir4.1 in the LHb bidirectionally regulates neuronal bursting and depression-like symptoms. Together, these results show that a glia-neuron interaction at the perisomatic space of LHb is involved in setting the neuronal firing mode in models of a major psychiatric disease. Kir4.1 in the LHb might have potential as a target for treating clinical depression.

Learning shapes the aversion and reward responses of lateral habenula neurons.

The lateral habenula (LHb) is believed to encode negative motivational values. It remains unknown how LHb neurons respond to various stressors and how learning shapes their responses. Here, we used fiber-photometry and electrophysiology to track LHb neuronal activity in freely-behaving mice. Bitterness, pain, and social attack by aggressors intensively excite LHb neurons. Aversive Pavlovian conditioning induced activation by the aversion-predicting cue in a few trials. The experience of social defeat also conditioned excitatory responses to previously neutral social stimuli. In contrast, fiber photometry and single-unit recordings revealed that sucrose reward inhibited LHb neurons and often produced excitatory rebound. It required prolonged conditioning and high reward probability to induce inhibition by reward-predicting cues. Therefore, LHb neurons can bidirectionally process a diverse array of aversive and reward signals. Importantly, their responses are dynamically shaped by learning, suggesting that the LHb participates in experience-dependent selection of behavioral responses to stressors and rewards.

Nicotine regulates activity of lateral habenula neurons via presynaptic and postsynaptic mechanisms

There is much interest in brain regions that drive nicotine intake in smokers. Interestingly, both the rewarding and aversive effects of nicotine are probably critical for sustaining nicotine addiction. The medial and lateral habenular (LHb) nuclei play important roles in processing aversion, and recent work has focused on the critical involvement of the LHb in encoding and responding to aversive stimuli. Several neurotransmitter systems are implicated in nicotine’s actions, but very little is known about how nicotinic acetylcholine receptors (nAChRs) regulate LHb activity. Here we report in brain slices that activation of nAChRs depolarizes LHb cells and robustly increases firing, and also potentiates glutamate release in LHb. These effects were blocked by selective antagonists of α6-containing (α6*) nAChRs, and were absent in α6*-nAChR knockout mice. In addition, nicotine activates GABAergic inputs to LHb via α4β2-nAChRs, at lower concentrations but with more rapid desensitization relative to α6*-nAChRs. These results demonstrate the existence of diverse functional nAChR subtypes at presynaptic and postsynaptic sites in LHb, through which nicotine could facilitate or inhibit LHb neuronal activity and thus contribute to nicotine aversion or reward.

Why depression and pain often coexist and mutually reinforce: Role of the lateral habenula

The interrelation of depression and pain is increasingly coming under scrutiny. Although the lateral habenula (LHb) is widely implicated in the pathogenesis of depression and pain, its role in the interaction of depression and pain remains unknown. Thus, the aim of current study was to investigate the role of LHb in rat depression-pain comorbidity. Single extracellular firing recording and immunofluorescence methods were used to compare firing rates and c-Fos expression of the LHb neurons in normal and model rats. Following subcutaneous injection of formalin into the hind paw to simulate natural pain, we assessed pain behavior in rats subjected to the chronic, unpredictable mild stress procedure (CUMS, a model of depression). Pain sensitivity in the model rats was increased over that of controls. These rats showed a significant increase in the firing activity of LHb neurons compared with normal rats. Significantly, about 73% of neurons with high discharge frequency in LHb of model rats were pain-activated neurons (PANs), and the firing rates of PANs were inhibited by intraperitoneal injection of a tricyclic antidepressant, clomipramine. Immunofluorescence showed that the percentage of c-Fos positive cells in LHb was significantly increased in rats receiving CUMS alone, rats receiving pain stimulation alone, and rats receiving both CUMS and pain stimulation, but especially the last. The interaction effect was inhibited by injection of clomipramine. The LHb lesion can improve both depression-like behavior and pain sensitivity in depression model rats with pain. These suggest that hyperactivity of the LHb neurons contributes to depression-pain comorbidity in rats.

High Frequency Electrical Stimulation of Lateral Habenula Reduces Voluntary Ethanol Consumption in Rats.

Background:Development of new strategies that can effectively prevent and/or treat alcohol use disorders is of paramount importance, because the currently available treatments are inadequate. Increasing evidence indicates that the lateral habenula (LHb) plays an important role in aversion, drug abuse, and depression. In light of the success of high-frequency stimulation (HFS) of the LHb in improving helplessness behavior in rodents, we assessed the effects of LHb HFS on ethanol-drinking behavior in rats.Methods:We trained rats to drink ethanol under an intermittent access two-bottle choice procedure. We used c-Fos immunohistochemistry and electrophysiological approaches to examine LHb activity. We applied a HFS protocol that has proven effective for reducing helplessness behavior in rats via a bipolar electrode implanted into the LHb.Results:c-Fos protein expression and the frequency of both spontaneous action potential firings and spontaneous excitatory postsynaptic currents were higher in LHb neurons of ethanol-withdrawn rats compared to their ethanol-naïve counterparts. HFS to the LHb produced long-term reduction of intake and preference for ethanol, without altering locomotor activity. Conversely, low-frequency electrical stimulation to the LHb or HFS applied to the nearby nucleus did not affect drinking behavior.Conclusions:Our results suggest that withdrawal from chronic ethanol exposure increases glutamate release and the activity of LHb neurons, and that functional inhibition of the LHb via HFS reduces ethanol consumption. Thus, LHb HFS could be a potential new therapeutic option for alcoholics.