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Psychedelics have emerged as a promising novel therapeutic approach for major depressive disorder (MDD). Altered activity and structural atrophy of the prefrontal cortex, hippocampus, and limbic structures are associated with depressive disorders. Psilocybin may reverse the loss of synaptic connections and restore the function of these brain regions. In this study, we investigated the effects of psilocybin on rat behavior, hippocampal neurogenesis, expression level of brain-derived neurotrophic factor (BDNF) and hypothalamic-pituitary-adrenal (HPA) axis activity. Psilocybin administered in two doses (0.6 mg/kg, s.c., 7 days apart) reversed anhedonia in stressed rats, produced antidepressant-like effects in the forced swim test (FST), and exerted anxiolytic activity in the light/dark box (LDB), elevated plus maze (EPM), and open field (OF) tests in stressed animals. Psilocybin induced hippocampal neurogenesis as evidenced by increasing the number of BrdU-positive cells (an exogenous marker of cell proliferation and survival), DCX-positive cells (a marker of immature neurons), and Ki-67-positive cells (an endogenous marker of cell proliferation) in stressed animals. Stress-induced reductions in BDNF expression levels appeared to be associated with normalization of HPA axis activity. These findings underscore the role of psilocybin-induced neuroplasticity in the antidepressant and anxiolytic mechanisms of psychedelics. Show less

Substance Use Disorders (SUD) have escalated into a global public health crisis, with their core pathology encompassing not only physiological dependence and a heightened risk of relapse, but also profound social cognitive impairments caused by chronic substance abuse. These impairments constitute a major barrier to rehabilitation yet remain largely overlooked in current treatment frameworks. This review develops and substantiates an innovative theoretical framework centered on the "Exercise-Irisin-Social Brain" axis. We propose a core pathway hypothesis: regular exercise can induce the release of the myokine irisin from skeletal muscle, which then enters the bloodstream and crosses the blood-brain barrier to act on the prefrontal cortex, which is the central hub of social cognition and executive function. Through potential mechanisms including the upregulation of brain-derived neurotrophic factor and the suppression of neuroinflammation, irisin may contribute to the repair of the executive function network that underlies higher-order social cognition, thereby improving social cognitive abilities and ultimately providing a supportive foundation for the reconstruction of social functioning in individuals with SUD. This new paradigm not only provides a testable biological pathway for understanding how exercise may repair the addicted brain, but also transcends the limitations of traditional models that focus primarily on withdrawal and relapse, by elevating rehabilitation goals to emphasize the restoration of social functioning. Show less

Exercise has been shown to support brain health, cognitive function, and increase levels of brain-derived neurotrophic factor (BDNF). While BDNF is known to support the central nervous system through improved brain metabolism, vasculature, neurotransmission and synaptic plasticity, the association between exercise-induced changes in BDNF concentrations and exercise-related cognitive improvements is still unclear. This study investigated the relationship between exercise-induced changes in plasma BDNF (pBDNF) and serum BDNF (sBDNF), and haemodynamic indicators of prefrontal cortex function in sedentary adults. Participants (n = 23, female = 7) were randomized into intervention (12-week cycling programme) and control groups (no intervention). Participants completed V̇O Show less

Chronic pain (CP) is increasingly recognized not only as a sensory and emotional condition but also as a significant contributor to cognitive dysfunction. Growing evidence indicates that CP-induced cognitive dysfunction arises from a cascade of neurobiological processes, including persistent neuroinflammation, neurotransmitter dysregulation, and impaired synaptic plasticity. These mechanisms particularly affect the hippocampus and medial prefrontal cortex (mPFC)-regions essential for memory, attention, and executive function. Neuroimaging studies have documented structural atrophy and disrupted network connectivity in these brain areas in CP patients. At the molecular level, pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) impair glutamatergic and GABAergic signaling, disrupt long-term potentiation (LTP), and inhibit neurogenesis. Additionally, dysregulation of brain-derived neurotrophic factor (BDNF) signaling exacerbates synaptic vulnerability, contributing to cognitive decline. These mechanistic overlaps are particularly relevant in aging populations and in Alzheimer's disease (AD), where CP may act as a risk factor. This review integrates clinical and preclinical findings on CP-related cognitive dysfunction, outlines key molecular mechanisms, and explores emerging therapeutic strategies targeting inflammation, neurotransmitter systems, and synaptic repair. Understanding the interaction between chronic pain and cognition is critical for developing precision treatments that address both nociceptive and neurodegenerative pathways. Show less

For decades, major depressive disorder was attributed to a deficit in monoamine neurotransmitters. Clinical latency of tricyclic and selective serotonin reuptake inhibitors, high nonresponse rates, and inconsistent genetic findings challenged this view and redirected research toward downstream biology. Preclinical work revealed that chronic stress triggers dendritic and spine loss in the hippocampus and prefrontal cortex, whereas all effective treatments-including slow-acting monoaminergic drugs, rapid-acting ketamine, electroconvulsive therapy, and aerobic exercise-restore synapse number and function through brain-derived neurotrophic factor, TrkB, and mTOR signaling. Human connectomic studies then reframed depression as a disorder of mistimed large-scale networks; targeted neuromodulation of nodes intrinsically anticorrelated with the subgenual cingulate provides proof of concept. Parallel findings in immunology and gut-brain science show that psychosocial stress, peripheral cytokines, and metabolic cues converge on the same plasticity pathways, dissolving the historical boundary between "reactive" and "endogenous" depression. Ketamine crystallizes this multiscale model: within minutes, it induces dendritic-spine formation, normalizes default-mode and limbic connectivity, and relieves symptoms within hours. We synthesize these lines of evidence into a framework of precision synaptic psychiatry, in which pharmacological, neuromodulatory, and lifestyle interventions are selected according to biomarkers that index glutamatergic tone, inflammatory load, or network dynamics. Future therapeutics will be judged less by the neurotransmitters they influence and more by their capacity to restore flexible, resilient brain circuitry. Show less

Physical exercise is widely recognized for reducing neuropathic pain. However, the interaction between the immune and opioidergic systems in supraspinal structures is still not fully understood. To evaluate the impact of opioid receptor blockade on the effects of low-intensity exercise on the sensory, cognitive, and emotional aspects of neuropathic pain after sciatic nerve injury. Male Swiss mice (2 months old) were submitted to sciatic nerve crush and divided into sedentary or exercised groups. The exercised groups performed treadmill running for two weeks, with or without naloxone pre-treatment to block opioid receptors. Sensory responses were assessed using the von Frey test, while cognitive and emotional-like behaviors were evaluated through the Mechanical Conflict-Avoidance System (MCAS) and open field test, respectively. Cytokine levels (IL-4, IL-10) and brain-derived neurotrophic factor (BDNF) were quantified in the brainstem and prefrontal cortex by ELISA. Exercise reduced mechanical hypersensitivity and improved performance in cognitive and exploratory tasks. These effects were prevented by naloxone administration. Exercise also increased IL-4, IL-10, and BDNF levels in supraspinal regions, while naloxone reversed these changes, indicating the involvement of μ-opioid receptors in exercise-induced immunomodulation. Low-intensity exercise promotes analgesia and neuroimmune regulation in neuropathic pain through supraspinal μ-opioid receptor activation. The blockade of these receptors abolishes the beneficial effects of exercise, reinforcing the interaction between opioidergic and immune systems in pain modulation. Show less

Rodent studies have shown that psychedelic drugs can enhance fear extinction. However, investigations to date have relied on normative aversive conditioning procedures, which limit their relevance to trauma-related memories, as these tend to be overgeneralized and resistant to extinction. Fear extinction depends on activity and plasticity within the infralimbic (IL) region of the medial prefrontal cortex and is regulated by brain-derived neurotrophic factor (BDNF). Ayahuasca (AYA), a brew containing the serotonergic psychedelic N,N-dimethyltryptamine (DMT), facilitates fear extinction in rodents and increases BDNF levels/signaling. Here, we investigated whether AYA attenuates extinction deficits and generalized fear induced by preconditioning restraint stress or high-intensity contextual fear conditioning, and whether these effects depend on BDNF-TrkB receptor signaling in the IL cortex. Adult male and female rats underwent the protocols above and received oral AYA one hour before each of the two extinction sessions conducted on consecutive days. Repeated administration of AYA containing 0.3 mg/kg of DMT enhanced extinction learning and its retention, effects that were abolished by bilateral intra-IL cortex infusion of an anti-BDNF antibody or the TrkB receptor antagonist ANA-12. AYA treatment also reduced fear generalization, an action that was BDNF-dependent in the IL cortex of females but not males. Overall, these findings indicate that AYA can modulate maladaptive fear memories through cortical mechanisms involving BDNF signaling, highlighting the potential of psychedelics as enhancers for extinguishing difficult-to-treat memories like those underlying post-traumatic stress disorder. Show less