Search Results (30)

Self-injurious behavior (SIB) is a devastating and potentially life-threatening action with high prevalence in adolescents and patients with neuropsychiatric disorders. Accumulating evidence indicates that disruptions in multiple cellular and circuit mechanisms underlie vulnerability to SIB. We used an inducible SIB rat model to study synaptic modification during SIB. At 0.5 and 1 h after bilateral injection of muscimol (1.0 μg/side) into the rat endopeduncular nucleus (EP, a rodent homolog of the internal globus pallidus (GPi)), which induced SIB in rats, expression of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) and the phosphorylation of GluA1 at Ser831 and Ser845 were tested in the lateral habenula (LHb), ventral tegmental area (VTA), nucleus accumbens (NAc), amygdala, and medial prefrontal cortex (mPFC) of the rat brain. We also tested if modulation of NAc activity with a GABA_A receptor agonist or antagonist or dopamine receptor agonist or antagonist or inhibiting the mPFC–NAc pathway affected SIB in rats. At 1 h after EP inhibition, total GluA1 expression and phosphorylated GluA1 were decreased in the mPFC, VTA, and NAc, but were increased in the amygdala compared with control rats. When the EP was inhibited by 0.2 μg/side muscimol, hyperactivation of the NAc increased SIB in rats. However, if the EP was inhibited by 1.0 μg/side muscimol, hyperactivation of the NAc had no effects on SIB. Inhibiting the mPFC–NAc pathway increased wound areas in rats with SIB. At the onset of SIB, excitatory synaptic transmission is simultaneously dampened in the reward and control circuitry (VTA, NAc, mPFC) and potentiated in the aversion circuitry (amygdala), indicating that SIB is associated with molecular signatures suggestive of a shift from reward to threat processing. Hyperactivation of the NAc increased SIB incidence in rats, but administration of dopamine receptor agonists and antagonists into the NAc did not significantly affect the incidence of SIB in this study. These findings provide a novel mechanistic perspective on SIB, offering a basis for the treatment of SIB. Full article

Light is the primary zeitgeber for circadian rhythms, and also through these mechanisms, is closely related to mood regulation. Bright light therapy (BLT) is a therapeutic intervention that specifically exploits this physiological mechanism. This review summarizes the clinical procedures of BLT, the mechanisms through which light influences circadian rhythms and mood, and the evidence supporting BLT in psychiatric disorders. BLT is administered by considering device distance, treatment duration, and light intensity. Through pathways originating in the retina and projecting to the Suprachiasmatic Nucleus (SCN), light might generate signals within the central nervous system that influence not only circadian regulation but also mood, via connections involving the limbic system, the lateral habenula, and interactions with the hormonal system. At the clinical level, the strongest evidence for BLT concerns seasonal affective disorder, but data also indicate antidepressant efficacy in major depressive disorder and bipolar disorder, with an excellent tolerability profile. Emerging evidence further suggests benefits for insomnia, and sporadic and heterogeneous findings have explored its potential role in other conditions. Future studies are needed to better define the role of BLT in additional psychiatric disorders and in specific symptom domains that may not adequately respond to standard treatments, such as sexual dysfunction. Full article

Objectives: Ketamine has demonstrated rapid and sustained antidepressant effects; however, its clinical utility is limited by the risk of addiction and systemic side effects. This study aimed to develop ketamine-loaded nanodroplets (Ket-NDs) with high encapsulation efficiency (EE) and stability for targeted low-dose intravenous (IV) administration in a mice model of depression. Low-intensity focused ultrasound (LIFU) was employed to induce transcranial, region-specific drug release in the lateral habenula (LHb). Methods: Ket-NDs were synthesized using a thin-film hydration method with sonication and emulsification, incorporating perfluoropentane as the core material. Characterization was performed using light microscopy, cryogenic scanning electron microscopy (cryo-SEM), transmission electron microscopy, and dynamic light scattering (DLS). Drug EE and loading efficiency (LE) were quantified by reversed-phase high-performance liquid chromatography. A chronic restraint stress model was established, and Ket-NDs were administered intravenously followed by LIFU targeting the LHb. Antidepressant efficacy and biosafety were systematically evaluated. Results: (1) Ket-NDs exhibited uniform spherical morphology and a narrow size distribution, as confirmed by DLS (particle size: 139.75 ± 9.43 nm; Polydispersity index: 0.225 ± 0.025) and cryo-SEM analysis (number-average diameter: 109.5 ± 10.4 nm). The zeta potential was −15.93 ± 5.906 mV, and the formulation remained stable under 4 °C storage. (2) Ket-NDs demonstrated high EE (78.25 ± 16.13%) and LE (15.55 ± 4.49%). (3) In depressive mice, IV administration of Ket-NDs followed by LIFU targeting the LHb significantly improved behavioral outcomes: increased locomotor activity in the open field test, elevated sucrose preference index, and reduced immobility time in the tail suspension test. (4) Safety assessments revealed no significant organ toxicity or brain tissue damage in ultrasound-exposed regions. Conclusions: In summary, this study developed stable Ket-NDs. When combined with LIFU, they enable precise regional drug delivery to the brain, showcasing a promising treatment strategy for depression with reduced systemic side effects. Full article

Maternal behavior encompasses a range of biologically driven responses whose expression and duration vary across species. Maternal responses rely on robust adaptive changes in the female brain, enabling mothers to engage in caregiving, nourishing, and offspring protection. Morphological and functional changes in the maternal brain enhance sensitivity to offspring cues, eliciting maternal behaviors, rewarding responses, and social processing stimuli essential for parenting. Maternal behavior comprises a range of biological responses that extend beyond basic actions, reflecting a complex, evolutionarily shaped neurobiological adaptation. These behaviors can be broadly categorized into direct behaviors, which are explicitly aimed at the care of the offspring, and indirect behaviors that, overall, ensure the protection, nourishment, and survival of the newborn. The secretion of main neuropeptide hormones, such as oxytocin (OT), prolactin (PRL), and placental lactogens (PLs), during the peripartum period, is relevant for inducing and regulating maternal responses to offspring cues, including suckling behavior. Although PRL is primarily associated with reproductive and parental functions in vertebrates, it also modulates distinct neural functions during pregnancy that extend from lactogenesis to adult neurogenesis, neuroprotection, and neuroplasticity, all of which contribute to preparing the maternal brain for motherhood and parenting interactions. Parvocellular OT-containing neurons in the paraventricular nucleus (PVN) and in the anterior hypothalamic nucleus (AHN) project axon collaterals to the medial preoptic area, which, in turn, projects to the nucleus accumbens (NACC) and lateral habenula (lHb) via the retrorubral field (RRF) and the ventral tegmental area (VTA), which mediate the motivational aspects of maternal responses to offspring cues. The reshaping process of the brain and neural networks implicated in motherhood depends on several factors, such as up- and downregulation of neuronal gene expression of bioactive peptide hormones (i.e., OT, PRL, TIP-39, galanin, spexin, pituitary adenylate cyclase-activating polypeptide (PACAP), corticotropin-releasing hormone (CRH), peptide receptors, and transcription factors (i.e., c-fos and pSTAT)) in target neurons in hypothalamic nuclei, mesolimbic areas, the hippocampus, and the brainstem, which, overall, regulate the expression of maternal behavior to offspring cues, as shown in postpartum female rodents. In this review, we describe the modulatory neuropeptides, the neural networks underlying peptide transmission systems, and cell signaling involved in parenthood. We highlight the dysregulation of neuropeptide hormones and their receptors in the central nervous system in relation to psychiatric disorders. Full article

Alcohol Use Disorder (AUD) profoundly impacts individuals and society, driven by neurobiological adaptations that sustain chronicity and relapse. Emerging research highlights neuroinflammation, particularly microglial activation, as a central mechanism in AUD pathology. Ethanol engages microglia—the brain’s immune cells—through key signaling pathways such as Toll-like receptor 4 (TLR4) and the NLRP3 inflammasome, triggering the release of proinflammatory cytokines (IL-1β, TNF-α, IL-6). These mediators alter synaptic plasticity in addiction-related brain regions, including the ventral tegmental area, nucleus accumbens, amygdala, and lateral habenula, thereby exacerbating cravings, withdrawal symptoms, and relapse risk. Rodent models reveal that microglial priming disrupts dopamine signaling, heightening impulsivity and anxiety-like behaviors. Human studies corroborate these findings, demonstrating increased microglial activation markers in postmortem AUD brains and neuroimaging analyses. Notably, sex differences influence microglial reactivity, complicating AUD’s neuroimmune landscape and necessitating sex-specific research approaches. Microglia-targeted therapies—including minocycline, ibudilast, GLP-1 receptor agonists, and P2X7 receptor antagonists—promise to mitigate neuroinflammation and reduce alcohol intake, yet clinical validation remains limited. Addressing gaps such as biomarker identification, longitudinal human studies, and developmental mechanisms is critical. Leveraging multi-omics tools and advanced neuroimaging can refine microglia-based therapeutic strategies, offering innovative avenues to break the self-sustaining cycle of AUD. Full article

The habenula (Hb) of the epithalamus is formed of the medial (MHb) and lateral (LHb) parts. The improper functioning of the Hb may lead to depression and anxiety. The glutamate excitotoxicity is accompanied by astroglia reactivity and leads to the damage of nervous system structures. The aim of the study was to assess the influence of monosodium glutamate (MSG) administrated subcutaneously to rats in doses of 2 g/kg b.w. (I) and 4 g/kg b.w. (II), on astroglia in the MHb and LHb. Based on immunohistochemical reactions, the morphology, number of astrocytes immunoreactive for glial fibrillary acidic protein (GFAP-IR) and S100β protein (S100β-IR), and their surface area, perimeter, number and length of processes, and cytoplasmic-nuclear immunostaining intensity for the studied proteins were assessed. In the MHb of animals receiving MSG, especially at a high dose, hypertrophy and an increase in the number of GFAP-IR and S100β-IR cells were demonstrated. In the LHb, only hypertrophy of processes in S100β-positive glia was observed. The immunostaining intensity increased in GFAP-IR glia and decreased in S100β-IR cells only in animals from group I. The results revealed that astroglia respond to MSG depending on its dose and the Hb part. This different behavior of glia may indicate their different sensitivity and resistance to damaging factors. Full article

The lateral hypothalamic area (LHA) serves as a central integrative hub for the regulation of energy homeostasis and motivational behaviors, including feeding and arousal. Recent advances in single-cell transcriptomics have revealed remarkable molecular heterogeneity within the LHA, identifying more than 30 distinct neuronal subtypes, such as GABAergic (LHA^Vgat), glutamatergic (LHA^Vglut2), orexin, melanin-concentrating hormone (MCH), and leptin receptor-expressing (LHA^Lepr) neurons. These neuronal populations sense peripheral metabolic signals—such as leptin, insulin, and glucose—both directly and indirectly, and they coordinate appropriate physiological and behavioral responses through local circuits and reciprocal connections with other hypothalamic nuclei. Furthermore, the LHA interfaces with extrahypothalamic regions, including the ventral tegmental area (VTA), nucleus accumbens (NAc), and lateral habenula (LHb), thereby linking metabolic state to reward processing and behavioral prioritization. In this review, we summarize and integrate recent molecular and functional findings to present a comprehensive view of the LHA as a dynamic, multifunctional center in the central regulation of metabolism. A deeper understanding of these mechanisms may offer new therapeutic avenues for addressing obesity and related metabolic disorders. Full article

Dysregulation in the stress-response system as a result of genetical mutation can provoke the manifestation of affective disorders under stress conditions. Mutations in the human DISC1 gene is one of the main risk factors of affective disorders. It was known that DISC1 regulates a large number of proteins including BMAL1, which is involved in the regulation of glucocorticoid synthesis in the adrenal glands and the sensitivity of glucocorticoid receptor target genes. Male mice with a point mutation Q31L in the Disc1 gene were exposed to chronic unpredictable stress (CUS), after which the behavioral and physiological stress response assessed. To assess whether there were any changes in BMAL1 in key brain regions involved in the stress response, immunohistochemistry was applied. It was shown that the Q31L mice had an aberrant behavioral response, especially to the 2 weeks of CUS, which was expressed in unchanged motor activity, increased time of social interaction, and alterations in anxiety and fear-related behavior. Q31L males did not show an increase in blood corticosterone levels after CUS and a decrease in body weight. Immunohistochemical analysis in intact Q31L mice revealed a decrease in BMAL1 immunofluorescence in the CA1 hippocampal area and lateral habenula. Thus, the Q31L mutation of the Disc1 gene disrupts behavioral and physiological stress response and the BMAL1 dysregulation may underlie it, so this protein can act as a molecular target for the treatment of affective disorders. Full article

Depression is a complex psychiatric disorder that has substantial implications for public health. The lateral habenula (LHb), a vital brain structure involved in mood regulation, and the N-methyl-D-aspartate receptor (NMDAR) within this structure are known to be associated with depressive behaviors. Recent research has identified transcription factor 7-like 2 (TCF7L2) as a crucial transcription factor in the Wnt signaling pathway, influencing diverse neuropsychiatric processes. In this study, we explore the role of TCF7L2 in the LHb and its effect on depressive-like behaviors in mice. By using behavioral tests, AAV-mediated gene knockdown or overexpression, and pharmacological interventions, we investigated the effects of alterations in TCF7L2 expression in the LHb. Our results indicate that TCF7L2 expression is reduced in neurons within the LHb of male ICR mice exposed to chronic mild stress (CMS), and neuron-specific knockdown of TCF7L2 in LHb neurons leads to notable antidepressant activity, as evidenced by reduced immobility time in the tail suspension test (TST) and forced swimming test (FST). Conversely, the overexpression of TCF7L2 in LHb neurons induces depressive behaviors. Furthermore, the administration of the NMDAR agonist NMDA reversed the antidepressant activity of TCF7L2 knockdown, and the NMDAR antagonist memantine alleviated the depressive behaviors induced by TCF7L2 overexpression, indicating the involvement of NMDAR. These findings offer novel insights into the molecular mechanisms of depression, highlighting the potential of TCF7L2 as both a biomarker and a therapeutic target for depression. Exploring the relationship between TCF7L2 signaling and LHb function may lead to innovative therapeutic approaches for alleviating depressive symptoms. Full article

The mesolimbic reward system originating from dopamine neurons in the ventral tegmental area (VTA) of the midbrain shows a profound reduction in function during cannabinoid withdrawal. This condition may underlie aversive states that lead to compulsive drug seeking and relapse. The lateral habenula (LHb) exerts negative control over the VTA via the GABA rostromedial tegmental nucleus (RMTg), representing a potential convergence point for drug-induced opponent processes. We hypothesized that the LHb–RMTg pathway might be causally involved in the hypodopaminergic state during cannabinoid withdrawal. To induce Δ⁹-tetrahydrocannabinol (THC) dependence, adult male Sprague–Dawley rats were treated with THC (15 mg/kg, i.p.) twice daily for 6.5–7 days. Administration of the cannabinoid antagonist rimonabant (5 mg/kg, i.p.) precipitated a robust behavioral withdrawal syndrome, while abrupt THC suspension caused milder signs of abstinence. Extracellular single unit recordings confirmed a marked decrease in the discharge frequency and burst firing of VTA dopamine neurons during THC withdrawal. The duration of RMTg-evoked inhibition was longer in THC withdrawn rats. Additionally, the spontaneous activity of RMTg neurons and of LHb neurons was strongly depressed during cannabinoid withdrawal. These findings support the hypothesis that functional changes in the habenulo–mesencephalic circuit are implicated in the mechanisms underlying substance use disorders. Full article

General anesthetics were first used over 170 years ago; however, the mechanisms of how general anesthetics induce loss of consciousness (LOC) remain unclear. Ciprofol, a novel intravenous anesthetic, has been developed by incorporating cyclopropyl into the chemical structure of propofol. This modification offers the benefits of rapid onset and minimal injection pain. Recent studies have revealed that the glutamatergic neurons of the lateral habenula (LHb) play a crucial role in modulating the LOC induced by propofol and sevoflurane. Nevertheless, the specific involvement of LHb in the anesthetic effects of ciprofol remains uncertain. Here, using targeted recombination in active populations (TRAP) combined with electroencephalogram/electromyography recordings and the righting reflex behavioral test, our study revealed that intravenous infusion of ciprofol for 1 h could lead to the induction of c-Fos expression in the LHb in mice. The combination of TRAP and gene ablation, aimed at selectively ablating ciprofol-activated neurons in the LHb, has been shown to facilitate the emergence of ciprofol anesthesia and decrease the proportion of delta waves during the emergence phase. Chemogenetic inhibition of these neurons produced a comparable effect, whereas chemogenetic activation resulted in the opposite outcome. Chemogenetic activation of ciprofol-activated neurons in the LHb delays the emergence of anesthesia and induces a deep hypnotic state during the emergence phase. Taken together, our findings suggest that LHb ciprofol-activated neurons modulate the state of consciousness and could potentially be targeted to manipulate consciousness during ciprofol anesthesia. Full article

The habenular complex is a diencephalic structure divided into the medial and lateral divisions that lie within the epithalamus of most vertebrates. This brain structure, whose activities are mainly regulated via inputs/outputs from and to the stria medullaris and the fasciculus retroflexus, plays a significant role in the modulation of anti-reward behaviors in both the rodent and human brain. Such anti-reward circuits are regulated by dopaminergic and serotonergic projections with several other subcortical and cortical regions; therefore, it is plausible that impairment to this key subcortical structure or its connections contributes to the pathogenesis of affective disorders. Current literature reveals the existence of structural changes in the habenula complex in individuals afflicted by such disorders; however, there is a need for more comprehensive investigations to elucidate the underlying neuroanatomical connections that underpin disease development. In this review article, we aim to provide a comprehensive view of the neuroanatomical differences between the rodent and human habenular complex, the main circuitries, and provide an update on the emerging roles of this understudied subcortical structure in the control of affective behaviors, with special emphasis to morbid conditions of the affective sphere. Full article

Chronic pain is a health problem that affects the ability to work and perform other activities, and it generally worsens over time. Understanding the complex pain interaction with brain circuits could help predict which patients are at risk of developing central dysfunctions. Increasing evidence from preclinical and clinical studies suggests that aberrant activity of the lateral habenula (LHb) is associated with depressive symptoms characterized by excessive negative focus, leading to high-level cognitive dysfunctions. The primary output region of the LHb is the ventral tegmental area (VTA), through a bidirectional connection. Recently, there has been growing interest in the complex interactions between the LHb and VTA, particularly regarding their crucial roles in behavior regulation and their potential involvement in the pathological impact of chronic pain on cognitive functions. In this review, we briefly discuss the structural and functional roles of the LHb–VTA microcircuit and their impact on cognition and mood disorders in order to support future studies addressing brain plasticity during chronic pain conditions. Full article

Elevated glucocorticoid levels triggered by stress potentially contribute to sleep disturbances in stress-induced depression. However, sleep changes in response to elevated corticosterone (CORT), the major glucocorticoid in rodents, remain unclear. Here, we investigated the effects of acute or chronic CORT administration on sleep using electroencephalogram (EEG) and electromyography (EMG) recordings in freely moving mice. Acute CORT exposure rapidly promoted wakefulness, marked by increased episodes and enhanced EEG delta power, while simultaneously suppressing rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, with the latter marked by decreased mean duration and reduced delta power. Prolonged 28-day CORT exposure led to excessive wakefulness and REM sleep, characterized by higher episodes, and decreased NREM sleep, characterized by higher episodes and reduced mean duration. EEG theta activity during REM sleep and delta activity during NREM sleep were attenuated following 28-day CORT exposure. These effects persisted, except for REM sleep amounts, even 7 days after the drug withdrawal. Elevated plasma CORT levels and depressive phenotypes were identified and correlated with observed sleep changes during and after administration. Fos expression significantly increased in the lateral habenula, lateral hypothalamus, and ventral tegmental area following acute or chronic CORT treatment. Our findings demonstrate that CORT exposure enhanced wakefulness, suppressed and fragmented NREM sleep, and altered EEG activity across all stages. This study illuminates sleep alterations during short or extended periods of heightened CORT levels in mice, providing a neural link connecting insomnia and depression. Full article

Understanding the mechanisms responsible for anxiety disorders is a major challenge. Avoidance behavior is an essential feature of anxiety disorders. The two-way avoidance test is a preclinical model with two distinct subpopulations—the good and poor performers—based on the number of avoidance responses presented during testing. It is believed that the habenula subnuclei could be important for the elaboration of avoidance response with a distinct pattern of activation and neuroinflammation. The present study aimed to shed light on the habenula subnuclei signature in avoidance behavior, evaluating the pattern of neuronal activation using FOS expression and astrocyte density using GFAP immunoreactivity, and comparing control, good and poor performers. Our results showed that good performers had a decrease in FOS immunoreactivity (IR) in the superior part of the medial division of habenula (MHbS) and an increase in the marginal part of the lateral subdivision of lateral habenula (LHbLMg). Poor performers showed an increase in FOS in the basal part of the lateral subdivision of lateral habenula (LHbLB). Considering the astroglial immunoreactivity, the poor performers showed an increase in GFAP-IR in the inferior portion of the medial complex (MHbl), while the good performers showed a decrease in the oval part of the lateral part of the lateral complex (LHbLO) in comparison with the other groups. Taken together, our data suggest that specific subdivisions of the MHb and LHb have different activation patterns and astroglial immunoreactivity in good and poor performers. This study could contribute to understanding the neurobiological mechanisms responsible for anxiety disorders. Full article