The hippocampus and prefrontal cortex (PFC) are connected in a reciprocal manner: whereas the hippocampus projects directly to the PFC, a polysynaptic pathway that passes through the nucleus reuniens (RE) of the thalamus relays inputs from the PFC to the hippocampus. The present study demonstrates that lesioning and/or inactivation of the RE reduces coherence in the PFC-hippocampal pathway, provokes an antidepressant-like behavioral response in the forced swim test and prevents, but does not ameliorate, anhedonia in the chronic mild stress (CMS) model of depression. Additionally, RE lesioning before CMS abrogates the well-known neuromorphological and endocrine correlates of CMS. In summary, this work highlights the importance of the reciprocal connectivity between the hippocampus and PFC in the establishment of stress-induced brain pathology and suggests a role for the RE in promoting resilience to depressive illness.

Introduction: This systematic review highlights that schizophrenia (SZ) manifests significant sex differences across neurobiological, clinical, treatment response, and adverse effect domains, underscoring the need for sex-specific considerations in both research and clinical practice.Methods: A systematic search was conducted following PRISMA guidelines, primarily through Pubmed, PsycINFO, Web of Science, and the Cochrane Library. Eligible studies on sex differences in patients with schizophrenia were included. Main search keywords were schizophrenia, sex differences, sex, gender, neurobiology, symptomatology, epidemiology, treatment response, adverse effects.Results: While lifetime prevalence is similar between men and women, the disorder’s trajectory diverges. Men typically experience illness onset approximately 3–5 years earlier than women, with more severe negative symptoms, worse social functioning, and higher rates of comorbid substance use disorders. By contrast, women often have later onset—including a secondary mid-life peak likely linked to declining estrogen—and tend to present with more affective symptoms. Neurobiologically, men with SZ exhibit more extensive structural brain abnormalities and cognitive impairment (especially in memory), whereas women benefit from a degree of neuroprotection possibly mediated by estrogen and distinct gene expression patterns. Hormonal influences appear pivotal, with estrogen’s neuroprotective effects potentially delaying onset and mitigating symptom severity in women, and low testosterone levels correlating with more pronounced negative symptoms in men. Treatment response also varies by sex: women with SZ generally respond to antipsychotics at lower doses with better clinical improvement and fewer relapses, whereas men often require higher doses due to faster drug metabolism and also typically face higher relapse risks. Notably, the treatment advantage of women diminishes after menopause. Adverse effect profiles differ as well: women with SZ are more prone to side effects such as antipsychotic-induced hyperprolactinemia, weight gain, and metabolic or cardiovascular complications, while men tend to experience more neurological side effects while also exhibiting lower treatment adherence.Discussion: These multidimensional sex differences underscore that all aspects of schizophrenia—from pathophysiology and presentation to therapy and side effect management—must be viewed through a sex-specific lens. Tailoring interventions to the needs of men and women patients is essential for optimizing outcomes and advancing personalized care.

Aromatase inhibitors block the conversion of androgens to oestrogens and are used for the treatment of hormone-responsive breast cancer in menopause a

Dopamine D4 receptor (D4R) mechanisms are implicated in psychiatric diseases characterized by cognitive deficits, including schizophrenia, ADHD, and autism. The cellular mechanisms are poorly understood, but impaired neuronal synchronization in cortical networks was proposed to contribute to these deficits. In animal experiments, D4R activation was shown to generate aberrant increased gamma oscillations and to reduce performance on cognitive tasks requiring functional prefrontal cortex (PFC) and hippocampus (HPC) networks. While fast oscillations in the gamma range are important for local synchronization within neuronal ensembles, long-range synchronization between distant structures is achieved by slow rhythms in the delta, theta, alpha ranges. The characteristics of slow oscillations vary between structures during cognitive tasks. HPC activity is dominated by theta rhythm, whereas PFC generates unique oscillations in the 2–4 Hz range. In order to investigate the role of D4R on slow rhythms, cortical activity was recorded in rats under urethane anesthesia in which slow oscillations can be elicited in a controlled manner without behavioral confounds, by electrical stimulation of the brainstem reticular formation. The local field potential segments during stimulations were extracted and subjected to fast Fourier transform to obtain power density spectra. The selective D4R agonist A-412997 (5 and 10 mg/kg) and antagonists L-745870 (5 and 10 mg/kg) were injected systemically and the peak power in the two frequency ranges were compared before and after the injection. We found that D4R compounds significantly changed the activity of both HPC and PFC, but the direction of the effect was opposite in the two structures. D4R agonist enhanced PFC slow rhythm (delta, 2–4 Hz) and suppressed HPC theta, whereas the antagonist had an opposite effect. Analogous changes of the two slow rhythms were also found in the thalamic nucleus reuniens, which has connections to both forebrain structures. Slow oscillations play a key role in interregional cortical coupling; delta and theta oscillations were shown in particular, to entrain neuronal firing and to modulate gamma activity in interconnected forebrain structures with a relative HPC theta dominance over PFC. Thus, the results of this study indicate that D4R activation may introduce an abnormal bias in the bidirectional PFC–HPC coupling which can be reversed by D4R antagonists.