Complex Three-Dimensional Rearing Environments Amplify Compensatory Plasticity Following Early Blindness

The neocortex has a remarkable capacity to alter its functional organization and connectivity in response to sensory loss, particularly if this loss occurs early in life. A key question is whether this cross-modal reorganization is driven by sensory deprivation or by enhanced use of the spared senses. We investigated how different rearing environments shape neural responses in primary somatosensory cortex (S1) of short-tailed opossums ( Monodelphis domestica ), following elimination of visual inputs through bilateral enucleation in early development. Early blind and sighted littermates of either sex were reared in enriched environments to promote active tactile exploration in three-dimensional space or in standard laboratory cages. In adulthood, both enriched groups showed adaptive changes in exploration patterns and gap crossing behaviors relative to standard-reared counterparts. Thus, early blind animals showed behavioral compensation when challenged by complex environments. Enriched rearing increased selectivity of S1 neural responses to whisker touch and altered receptive field shapes such that they were less horizontally anisotropic. This shift was strongest in enriched early blind animals, enhancing tuning along the behaviorally relevant horizontal axis more than in standard-reared early blind animals. Thus, alterations in receptive fields of neurons in S1 following early blindness were amplified by environmental complexity. Sighted opossums reared with enrichment also showed similar whisker receptive field plasticity, though to a slightly lower degree. These results demonstrate that the rearing environment strongly influences the reorganization of cortex that processes inputs from the spared senses, underscoring the role of experience in directing compensatory plasticity following early sensory loss.

doi.org

Sustaining Drug Discovery Amid the Limits of Alzheimer's Disease Immunotherapies

Accumulation of insoluble extracellular amyloid-β (Aβ) plaques and intraneuronal fibrillary hyperphosphorylated tau fibrils in the brain are widely believed to contribute to the progressive neurodegeneration and neuronal loss characteristic of the Alzheimer’s disease and the associated dementia. Anti-amyloid immunotherapies that reduce cerebral Aβ burden in affected individuals have been approved based on biological outcomes from clinical trials. However, the extent to which Aβ clearance translates into improved meaningful clinical, cognitive, and functional benefit versus risk and cost is unclear based on available data. Here, the critical barriers that limit the impact of anti-amyloid immunotherapies, including aducanumab, lecanemab, and donanemab, are discussed. Treatment slows cognitive decline by ∼20–30% in certain patient subsets, but absolute improvements in cognitive and functional outcomes remain modest. Independent analyses of how treatment impacts health span suggests statistically significant trial results may not translate into significant real-world benefit. Response is most significant in cases of early-stage disease where levels of copathology tau are low. Edema and brain hemorrhage occur frequently, particularly in carriers of APOE-e4 alleles, an established genetic risk factor for Alzheimer's disease, raising safety concerns which led to some regulators banning treatment in this patient group. Strict clinical trial eligibility criteria, high treatment costs relative to patient benefit, intensive during-treatment monitoring, and the absence of population-level screening programs further limit treatment accessibility and generalizability. Emerging evidence of accelerated brain atrophy and immunotherapy tolerance further complicates benefit–risk consultation. Sustaining drug- discovery pipelines by exploring combination therapies, tau-targeted approaches, drug repositioning, and novel small molecules through will be essential to provide comprehensive treatment options and personalized treatment plans for affected patients.

doi.org

c-Maf Deletion in Cortical Somatostatin, But Not Parvalbumin, Interneurons Leads to Absence-Like Epileptiform Activity in Mice

Mafb and c-Maf transcription factors (TFs) are expressed in medial ganglionic eminence (MGE) lineages, beginning in progenitors and continuing into mature GABAergic parvalbumin-positive (PV+) and somatostatin-positive (SST+) cortical interneurons (CINs). Deleting Mafb and c-Maf in MGE before SST versus PV fate specification causes developmental anomalies, including altered numbers of CINs and seizure phenotypes, but the specific contributions of these TFs in postmitotic SST+ and PV+ CINs to epilepsy remain unknown. To address this, we conditionally deleted Mafb or c-Maf in SST+ or PV+ interneurons after interneuron fate specification in female and male mice. Deletion of c-Maf, but not Mafb, in SST+ cells was associated with reduced synaptic excitation onto these cells and with spontaneous spike-and-wave discharges, consistent with absence-like seizures. In contrast, deletion of Mafb in SST+ CINs reduced their density in superficial cortical layers but did not induce epilepsy. Neither c-Maf nor Mafb deletion in PV+ CINs produced major electrophysiological or histological abnormalities in the somatosensory cortex. These findings identify a specific requirement for c-Maf in modulating synaptic excitation of SST+ interneurons and show that its loss in SST+ cells is associated with the development of absence-like epileptiform activity in vivo. Together, our results refine the understanding of how transcriptional programs shape interneuron function in the mature cortex and highlight c-Maf/MAF-dependent pathways as candidates for investigation in epilepsy genetics.

doi.org

Limited Contribution of the Lactate Receptor HCAR1 to Exercise-Induced Behavioral and Hippocampal Adaptations

Physical exercise influences hippocampal function and behavior, and lactate has emerged as a candidate signaling molecule linking metabolic activity to neuroplasticity. One proposed mediator is the hydroxycarboxylic acid receptor 1 (HCAR1), but its contribution to behavioral and hippocampal adaptations to exercise remains unclear. We combined studies of HCAR1 knock-out (KO) mice with analyses of human postmortem hippocampal tissue to assess whether HCAR1 is required for behavioral or synaptic responses to exercise and to characterize its spatial distribution in the human hippocampus. Wild-type and HCAR1 KO mice of either sex underwent a 3 week high-intensity interval treadmill program or sedentary handling. Behavioral responses were assessed using the splash test and three-chamber sociability assay, and dentate gyrus (DG) field recordings evaluated synaptic transmission and excitability. In parallel, HCAR1 expression was quantified in the hippocampal tissue from individuals with major depressive disorder (MDD) and nondepressed controls. Exercise reduced grooming and increased locomotion similarly across genotypes, indicating largely preserved behavioral responses in the absence of HCAR1. HCAR1 KO control mice exhibited delayed initiation of social interaction, not observed in exercised mice. Electrophysiology revealed subtle genotype-dependent differences in DG responsiveness following exercise, without major changes in short-term plasticity. In the small available cohort, HCAR1 showed a predominantly perivascular distribution across hippocampal subregions in both MDD and control cases. Together, these findings indicate that HCAR1 is not required for the primary behavioral and synaptic outcomes measured here following exercise, while leaving open a contribution to more specific aspects of hippocampal function under these or other conditions.

doi.org

Functional Characterization of Dopamine Projections across Nucleus Accumbens Subregions in Reward-Related, Anxiety-Like, and Locomotor Behaviors

Mesolimbic dopamine (DA) neurons projecting to the nucleus accumbens (NAc) have traditionally been viewed as a functionally homogeneous reward pathway. However, recent evidence reveals functional heterogeneity, with DA projections to specific NAc subregions responding not only to rewards but also to aversive and safety-related stimuli. The extent to which DA projections across distinct NAc subregions differentially promote reward, aversion and anxiety-related behavior remains incompletely understood. To address this question, we performed optogenetic inhibition of DA terminals across different NAc subregions during real-time place preference and anxiety-related tests in predominantly male mice. We found that inhibition of DA terminals across all NAc subregions produced robust place avoidance, indicating that DA input to each subregion is similarly reinforcing and that its inhibition is aversive. In contrast, DA terminal inhibition resulted in subregion-specific effects on locomotor activity but had no acute effect on anxiety-like behavior. Together, these findings suggest that while DA projections to the NAc are uniformly reinforcing, they exhibit subregion-specific roles in regulating locomotor activity and have no acute effect in modulating anxiety, highlighting both common and diverging functions of distinct mesolimbic DA systems.

doi.org

Emergent Multidien Cycles From Partial Circadian Synchrony

Over the past decades, chronobiology has attracted great attention thanks to the elucidation of the molecular mechanisms underpinning the circadian cycle. Now, growing evidence suggests that cycles longer than circadian, so-called “multidien” cycles, are of crucial importance in physiological fluctuations spanning multiple days with repercussions in health and disease. Unlike circadian clocks, multidien cycles may not be genetically encoded, given their heterogeneity within and across individuals and systems. Here, we propose that multidien cycles may be generated by the interaction between partially coupled circadian oscillators. To demonstrate this possibility theoretically, we use a ring model of coupled circadian oscillators and study how synchrony within this network evolves over time. We found that a free-running, about-weekly period robustly emerges from the network’s dynamics. A range of additional multidien cycles resulted from subtle variations in the coupling parameters within the network with periodicities reminiscent of those observed across different species. Thus, our model of emergent multidien cycles from partial circadian synchrony constitutes a credible hypothesis for explaining the timing of a myriad of events on the scale of weeks and months in health and disease.

doi.org

Experience-Dependent Plasticity of Periglomerular Cells in the Olfactory Bulb

The olfactory bulb (OB) serves as the first relay station that processes odor information. Within the OB, odor representations are dynamically modulated by reciprocal synapses between excitatory mitral and tufted (M/T) cells and local inhibitory interneurons. Among these interneurons, periglomerular cells (PGCs) are GABAergic neurons located in the glomerular layer that provide inhibitory inputs to M/T cells. Although their anatomical and molecular properties have been extensively characterized, the in vivo dynamics of PGCs during odor processing and learning remain poorly understood. To address this question, we performed in vivo two-photon calcium imaging of awake male mice to monitor the activity of individual PGCs during odor-associated tasks. PGCs exhibited robust and odor-specific responses that varied among individual odorants. Repeated passive odor exposure reduced the number of odor-responsive PGCs while preserving their odor selectivity. In contrast, active odor discrimination learning expanded the population of odor-responsive PGCs and enhanced response amplitude. Furthermore, discriminating highly similar odor mixtures recruited a broader ensemble of PGCs with lower selectivity, but this representation sharpened over training, resulting in fewer yet more selective PGCs. These findings demonstrate the experience-dependent features of PGCs and reveal their critical role in tuning olfactory processing. Our study provides fundamental insights into how inhibitory circuits regulate sensory representations underlying adaptive odor-guided behaviors.

doi.org

Translational Profiling of Drd2-Expressing Populations Reveals Molecular Heterogeneity of Dentate Gyrus Mossy Cells along the Dorsoventral Axis

Hilar mossy cells (MCs) are crucial for integrating and propagating signals across the hippocampal dorsoventral axis, mediating cognitive and affective processing. While MCs exhibit profound dorsoventral differences in their projections, physiology, and behavioral roles, the molecular basis underlying this functional specialization remains largely unexplored. To address this gap, we used translating ribosome affinity purification (TRAP) in male mice to systematically compare the translatome of Drd2 -expressing, MC-enriched populations along the dorsoventral axis. This analysis revealed distinct translational signatures with 1,442 genes enriched in dorsal and 1,337 genes in ventral Drd2 -expressing, MC-enriched populations. Pathway analysis demonstrated significant functional segregation along the dorsoventral axis. The dorsal population is notably enriched for genes linked to neuronal connectivity and synaptic transmission, whereas the ventral counterpart shows enrichment in genes associated with energy metabolism and cellular maintenance. Specifically, we identified a subset of dorsal enriched genes, including neurotransmitter receptors, ion channels, and axon guidance regulators, contrasting with ventral enriched genes highly related to glucose/fatty acid metabolism, oxidative phosphorylation, and exocytosis. We further predicted distinct sets of upstream transcriptional regulators activated in each subpopulation, providing insights into the regulatory networks that may drive molecular divergence. Our findings provide a translatomic basis for the dorsoventral heterogeneity of Drd2-expressing neurons that include MCs, offering molecular signatures associated with their differential contributions to hippocampal function.

doi.org

Movement Disorder Patients with Depression Have Altered Corticostriatal Alpha-Beta Power Response to Reward and Loss

Depression is a common comorbidity in movement disorders such as Parkinson's disease (PD) and essential tremor (ET). Altered reward signaling contributes to core depression symptoms such as anhedonia, but the specific neural activity patterns underlying these processes and how they manifest in comorbid movement disorders are incompletely understood. Fourteen PD and 16 ET patients (22 male, 8 female) participated while undergoing deep brain stimulation surgery. Subjects completed a working memory task and received visual feedback about response accuracy while signals were recorded from traversed structures [caudate and/or dorsolateral prefrontal cortex (DLPFC)]. Preoperative Beck Depression Inventory-II (BDI-II) scores of ≥14 indicated elevated depression symptoms. Using cluster-based permutation testing, we identified time and frequency ranges in which oscillatory power significantly differed during reward versus loss feedback. We then used two-way ANOVAs and linear mixed effects models to assess how these power changes differed based on movement disorder and depression severity. Caudate and DLPFC alpha-beta (8–30 Hz) power increased during reward feedback. In both regions, this increase was attenuated in depressed subjects (caudate difference = −0.22, 95% CI = −0.32 to −0.13; DLPFC difference = −0.10, 95% CI = −0.16 to −0.045). BDI-II score was a negative predictor of reward- and loss-related corticostriatal alpha-beta power (caudate estimate = −0.014, 95% CI = −0.020 to −0.0078; DLPFC estimate = −0.0075, 95% CI = −0.012 to −0.0029). Specific to PD, depressed patients had greater decreases in DLPFC alpha-beta power following loss feedback than nondepressed patients (difference = −0.10, 95% CI = −0.17 to −0.027). Our findings suggest that altered corticostriatal alpha-beta power may contribute to reward dysfunction in depression in patients with movement disorders.

doi.org