Search Results (50)

Evidence of possible cerebellar involvement in spatial processing, place learning and other types of higher order functions comes mainly from clinical observations, as well as from mutant mice and lesion studies. The latter, in particular, have reported deficits in spatial learning and memory following surgical or neurotoxic cerebellar ablation. However, the low specificity of such manipulations has often made it difficult to precisely dissect the cognitive components of the observed behaviors. Likewise, due to conflicting data coming from lesion studies, it has not been possible so far to conclusively address whether a cerebellar dysfunction is sufficient per se to induce learning deficits, or whether concurrent damage to other regulatory structure(s) is necessary to significantly interfere with cognitive processing. In the present study, the immunotoxin 192 IgG-saporin, selectively targeting cholinergic neurons in the basal forebrain and a subpopulation of cerebellar Purkinje cells, was administered to adult rats bilaterally into the basal forebrain nuclei, the cerebellar cortices or both areas combined. Additional animals underwent injections of the toxin into the lateral ventricles. Starting from two–three weeks post-lesion, the animals were tested on paradigms of motor ability as well as spatial learning and memory and then sacrificed for post-mortem morphological analyses. All lesioned rats showed no signs of ataxia and no motor deficits that could impair their performance in the water maze task. The rats with discrete cerebellar lesions exhibited fairly normal performance and did not differ from controls in any aspect of the task. By contrast, animals with double lesions, as well as those with 192 IgG-saporin given intraventricularly did manifest severe impairments in both reference and working memory. Histo- and immunohistochemical analyses confirmed the effects of the toxin conjugate on target neurons and fairly similar patterns of Purkinje cell loss in the animals with cerebellar lesion only, basal forebrain-cerebellar double lesions and bilateral intraventricular injections of the toxin. No such loss was by contrast seen in the basal forebrain-lesioned animals, whose Purkinje cells were largely spared and exhibited a normal distribution pattern. The results suggest important functional interactions between the ascending regulatory inputs from the cerebellum and those arising in the basal forebrain nuclei that would act together to modulate the complex sensory–motor and cognitive processes required to control whole body movement in space. Full article

The basal forebrain (BF)-hippocampus (HPC) circuit is indispensable for learning and memory, and in vitro models are essential for dissecting its age-related decline. Nonetheless, current culture methods endure brief survival or confine cells to two dimensions, leaving the circuit’s progressive degeneration refractory to long-term investigation. Here, we developed a simple, three-dimensional (3D) compartmentalized co-culture model that mimics the anatomical organization of BF and HPC neurons. Results demonstrate that basal forebrain cholinergic neurons (BFCNs) co-cultured with primary HPC neurons remain viable for more than two months without exogenous growth factors, significantly promoting BFCNs growth, polarity development, and functional maturation. In this system, BFCNs somata were confined within the hydrogel, whereas cholinergic axons extended toward adjacent hippocampal area, reaching 1681.9 ± 351.8 μm by week 5—significantly longer than in BFCNs monocultures. This model can successfully recapitulate age-dependent progressive neuronal degeneration during long-term culture, validating this long-term co-culture as a platform for studying circuit aging and degeneration. Therefore, this low-cost and highly physiological platform provides a new avenue for in-depth investigations into the mechanisms of neurodegenerative diseases. Full article

Down syndrome (DS), stemming from the triplication of human chromosome 21, results in intellectual disability, with early mid-life onset of Alzheimer’s disease (AD) pathology. Early interventions to reduce cognitive impairments and neuropathology are lacking. One modality, maternal choline supplementation (MCS), has shown beneficial effects on behavior and gene expression in neurodevelopmental and neurodegenerative disorders, including trisomic mice. Loss of basal forebrain cholinergic neurons (BFCNs) and other DS/AD relevant hallmarks were observed in a well-established trisomic model (Ts65Dn, Ts). MCS attenuates these endophenotypes with beneficial behavioral effects in trisomic offspring. We postulate MCS ameliorates dysregulated cellular mechanisms within vulnerable BFCNs, with attenuation driven by novel gene expression. Here, choline acetyltransferase immunohistochemical labeling identified BFCNs in the medial septal/ventral diagonal band nuclei of the basal forebrain in Ts and normal disomic (2N) offspring at ~11 months of age from dams exposed to MCS or normal choline during the perinatal period. BFCNs (~500 per mouse) were microisolated and processed for RNA-sequencing. Bioinformatic assessment elucidated differentially expressed genes (DEGs) and pathway alterations in the context of genotype (Ts, 2N) and maternal diet (MCS, normal choline). MCS attenuated select dysregulated DEGs and relevant pathways in aged BFCNs. Trisomic MCS-responsive improvements included pathways such as cognitive impairment and nicotinamide adenine dinucleotide signaling, among others, indicative of increased behavioral and bioenergetic fitness. Although MCS does not eliminate the DS/AD phenotype, early choline delivery provides long-lasting benefits to aged trisomic BFCNs, indicating that MCS prolongs neuronal health in the context of DS/AD. Full article

Memory is a fundamental neurological function, essential for animal survival. Over the course of vertebrate evolution, elaborations in the forebrain telencephalon created new memory mechanisms, meaning basal vertebrates such as amphibians must have a less sophisticated system of memory acquisition, storage, and retrieval than the well-known hippocampal-based circuitry of mammals. Personality also appears to be a fundamental vertebrate trait and is generally defined as consistent individual behavior over time and across life history stages. In anuran amphibians (frogs), personality studies generally ask whether adult frogs retain the personality of their tadpole stage or whether personality shifts with metamorphosis, an idea behavioral ecologists term adaptive decoupling. Using a multidisciplinary perspective and recognizing there are ~7843 species of frogs, each with some molecular, morphological, physiological, or behavioral feature that makes it unique, we review, clarify, and provide perspective on what we collectively know about memory and personality and their mechanisms in anuran amphibians. We propose four working hypotheses: (1) as tadpoles grow, new telencephalic neurons become integrated into functional networks, producing behaviors that become more sophisticated with age; (2) since carnivores tend to be more bold/aggressive than herbivores, carnivorous anuran adults will be more aggressive than herbivorous tadpoles; (3) each amphibian species, and perhaps life history stage, will have a set point on the Shy–Bold Continuum; and (4) around this set point there will be a range of individual responses. We also suggest that several factors are slowing our understanding of the variety and depth of memory and personality possibilities in anurans. These include the scala natura approach to comparative studies (i.e., the idea that one frog represents all frogs); the assumption that amphibians are no more than simple reflex machines; that study species tend to be chosen more for convenience than taxonomic representation; and that studies are designed to prove or disprove a construct. This latter factor is a particular hindrance because what we are really seeking as scientists is not the confirmation or refutation of ideas, but rather what those ideas are intended to produce, which is understanding. Full article

Cholinergic projections from the basal forebrain to the cortex and hippocampus play a critical role in cognitive functions, many of which rely on signaling through the alpha7 nicotinic acetylcholine receptor (α7nAChR). The Alzheimer’s disease (AD) brain is characterized by the profound impairment of the basal forebrain cholinergic system, including alterations in the levels of α7nAChR in various brain areas. In addition, α7nAChR binds with high affinity to beta amyloid (Aβ), suggesting α7nAChR might mediate some of Aβ’s effects in the brain. Under normal physiological conditions, the interaction between Aβ and α7nAChR appears to be beneficial, supporting normal neurotransmission, synaptic plasticity, and memory functions. However, when levels of Aβ are pathologically elevated, their interaction leads to deleterious effects, implicating α7nAChR in the pathophysiology of AD. In addition to expression in neurons, α7nAChR is expressed in astrocytes and microglia, where it serves as a key component of a cholinergic pathway that regulates neuroinflammation. This review article will cover the role of α7nAChR in neurons, astrocytes and microglia under normal conditions, summarize changes in the expression or function of α7nAChR in neurons and glia in the AD brain, and discuss cell-type specific contributions of α7nAChR to AD pathology with an emphasis on interactions of α7nAChR with Aβ. Full article

Parvalbumin (PV) neurons in the basal forebrain (BF) orchestrate cognitive functions via extensive brain-wide projections. However, the age-related cognitive decline of their anatomical circuits remains poorly understood. Here, we employed viral tracing and fluorescence micro-optical sectioning tomography (fMOST) to reveal the vulnerability of the BF-PV circuits during aging. Quantitative whole-brain fluorescence intensity analysis revealed that BF-PV neurons projecting to the medial mammillary nucleus (MM) exhibited pronounced age-dependent neurodegeneration, characterized by 81.1% fiber loss and axonal swelling, while those innervating hippocampal CA1 showed a 70.3% reduction in fiber density. Optogenetic interventions demonstrated that selective activation of the BF^PV-MM circuit can ameliorate cognitive deficits in old mice, significantly improving the novel object recognition index and its change rate. In contrast, modulation of the BF^PV-CA1 circuit showed no significant effects. Moreover, with the whole-brain dataset, we reconstructed the morphology of individual neurons, revealing structural divergence between MM- and CA1-projecting PV neurons. Taken together, our results delineate the optogenetic-targeted activation of the BF^PV-MM circuit, which can ameliorate age-related cognitive decline and provide both theoretical and therapeutic foundations for targeting neurodegenerative disorders. Full article

: Alzheimer’s disease (AD) is a neurodegenerative disorder closely associated with aging, and its pathogenesis involves the interaction of multidimensional pathophysiologic processes. This review outlines the core mechanisms linking aging and AD. The amyloid cascade hypothesis emphasizes that abnormal deposition of amyloid-β (Aβ) triggers neuronal damage and synaptic dysfunction, which is exacerbated by aging-associated declines in protein clearance. Neuroinflammation, a synergistic pathogenetic factor in AD, is mediated by microglia activation, creating a vicious cycle with Aβ and tau pathology. The cholinergic hypothesis states that the degeneration of cholinergic neurons in the basal forebrain can lead to acetylcholine deficiency, which is directly associated with cognitive decline. Endothelial disorders promote neuroinflammation and metabolic waste accumulation through blood–brain barrier dysfunction and cerebral vascular abnormalities. In addition, glutamate-mediated excitotoxicity and mitochondrial dysfunction (e.g., oxidative stress and energy metabolism imbalance) further lead to neuronal death, and aging-associated declines in mitochondrial autophagy exacerbate such damage. This review also explores the application of animal models that mimic AD and aging in studying these mechanisms and summarizes therapeutic strategies targeting these pathways. Future studies need to integrate multi-targeted therapies and focus on the role of the aging microenvironment in regulating AD pathology in order to develop more effective early diagnosis and treatment options. Full article

Familial Alzheimer’s disease (FAD) is a complex multifactorial disorder clinically characterized by cognitive impairment and memory loss. Pathologically, FAD is characterized by intracellular accumulation of the protein fragment Aβ42 (iAβ), hyperphosphorylated microtubule-associated protein TAU (p-TAU), and extensive degeneration of basal forebrain cholinergic neurons of the nucleus basalis of Meynert (NbM) and the medial septal nucleus (MSN), mainly caused by mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and PSEN2 gene. Since the dopaminergic system may contribute to FAD symptoms, alterations in the nigro-hippocampal pathway may be associated with cognitive impairment in FAD. Interestingly, p-α-synuclein (p-α-Syn), Aβ, and p-TAU have been found to coexist in vulnerable regions of postmortem AD brains. However, the mechanism by which Aβ, p-TAU, and α-Syn coexist in DAergic neurons in AD brains has not been determined. We generated PSEN1 I416T dopaminergic-like neurons (DALNs) from I416T menstrual stromal cells (MenSCs) in NeuroForsk 2.0 medium for 7 days and then cultured them in minimal culture medium (MCm) for another 4 days. On day 11, DALNs were analyzed for molecular and pathological markers by flow cytometry and fluorescence microscopy. We found that mutant DALNs showed increased accumulation of iAβ as well as increased phosphorylation of TAU at S202/T205 compared to WT DALNs. Thus, mutant DALNs exhibited typical pathological hallmarks of Alzheimer’s disease. Furthermore, PSEN1 I416T DALNs showed concomitant signs of OS as evidenced by the appearance of oxidized sensor protein DJ-1 (i.e., DJ-1C106-SO₃) and apoptotic markers TP53, pS63-c-JUN, PUMA, and cleavage caspase 3 (CC3). Notably, these DALNs exhibited PD-associated proteins such as intracellular accumulation of α-Syn (detected as aggregates of pS129-α-Syn) and phosphorylation of LRRK2 kinase at residue S935. In addition, mutant DALNs showed a 17.16- and 6.17-fold decrease in DA-induced Ca²⁺ flux, compared to WT DALNs. These observations suggest that iAβ and p-TAU, together with p-α-Syn, and p-LRRK2 kinase, may damage DAergic neurons and thereby contribute to the exacerbation of neuropathologic processes in FAD. Remarkably, the LRRK2 inhibitor PF-06447475 (PF-475) significantly reversed PSEN1 I416T-induced neuropathological markers in DAergic neurons. PF-465 inhibitor reduced iAβ, oxDJ-1C106-SO₃, and p-TAU. In addition, this inhibitor reduced pS935-LRRK2, pS129-αSYN, pS63-c-JUN, and CC3. We conclude that the observed neuroprotective effects of PF-475 are due to direct inhibition of LRRK2 activity and that the LRRK2 protein is upstream of the molecular cascade of apoptosis and proteinopathy. Our results suggest that PF-475 is an effective neuroprotective agent against endogenous PSEN1 I416T-induced neurotoxicity in DALNs coexisting with Parkinson’s disease markers. Therefore, PF-475 may be of great therapeutic value in FAD. Full article

Background and Objectives: Human immunodeficiency virus (HIV) has a profound impact on the central nervous system (CNS), contributing to cognitive impairment and depressive symptoms even in individuals receiving combination antiretroviral therapy (cART). This study aimed to investigate the associations between brain parenchymal volumes and neuropsychological outcomes, specifically focusing on cognitive function and depressive symptoms in HIV-positive males. Materials and Methods: A total of 48 male participants underwent cognitive assessment using the Mini-Mental State Examination (MMSE), while depressive symptoms were evaluated in 35 participants using the Beck Depression Inventory (BDI). Volumetric brain analysis was conducted through automated imaging software, volBrain (Version 1.0, published on 23 November 2021), ensuring high consistency and accuracy. Statistical analyses included Pearson correlation to identify relationships between brain volumes and neuropsychological outcomes, emphasizing key regions like the basal forebrain and cingulate gyrus. Results: Significant trends were observed between basal forebrain volume and MMSE scores, emphasizing the role of this region in cognitive regulation. Additional correlations were found with the anterior and middle cingulate gyri, which are crucial for executive functioning and attentional control. Notably, smaller right basal forebrain volumes were associated with greater depressive symptom severity, suggesting the region’s specific involvement in mood regulation. These findings highlight the dual impact of HIV on cognitive and emotional health, with structural vulnerabilities in key brain regions playing a central role. Conclusions: This study underscores the selective vulnerability of certain brain regions, such as the basal forebrain and cingulate gyrus, to HIV-associated neurodegeneration. The results highlight the importance of integrating neuroimaging and neuropsychological assessments in routine clinical care for HIV-positive individuals. The study emphasizes the importance of early detection and targeted interventions to address neuropsychological challenges in this population, with a call for further research in larger and more diverse cohorts. Full article

Background: Perfluorooctane sulfonic acid (PFOS), a widely used industrial chemical, was reported to induce memory and learning process dysfunction. Some studies tried to reveal the mechanisms that mediate these effects, but how they are produced is still unknown. Basal forebrain cholinergic neurons (BFCN) maintain cognitive function and their selective neurodegeneration induces cognitive decline, as observed in Alzheimer’s disease. PFOS was reported to disrupt cholinergic and glutamatergic transmissions and thyroid hormone action, which regulate cognitive processes and maintain BFCN viability. Objective/Methods: To evaluate PFOS neurodegenerative effects on BFCN and the mechanisms that mediate them, SN56 cells (a neuroblastoma cholinergic cell line from the basal forebrain) were treated with PFOS (0.1 µM to 40 µM) with or without thyroxine (T3; 15 nM), MK-801 (20 µM) or acetylcholine (ACh; 10 µM). Results: In the present study, we found that PFOS treatment (1 or 14 days) decreased thyroid receptor α (TRα) activity by decreasing its protein levels and increased T3 metabolism through increased deiodinase 3 (D3) levels. Further, we observed that PFOS treatment disrupted cholinergic transmission by decreasing ACh content through decreased choline acetyltransferase (ChAT) activity and protein levels and through decreasing muscarinic receptor 1 (M1R) binding and protein levels. PFOS also disrupted glutamatergic transmission by decreasing glutamate content through increased glutaminase activity and protein levels and through decreasing N-methyl-D-aspartate receptor subunit 1 (NMDAR1); effects mediated through M1R disruption. All these effects were mediated through decreased T3 activity and T3 supplementation partially restored to the normal state. Conclusions: These findings may assist in understanding how PFOS induces neurodegeneration, and the mechanisms involved, especially in BFCN, to explain the process that could lead to cognitive dysfunction and provide new therapeutic tools to treat and prevent its neurotoxic effects. Full article

Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia. There is currently no effective treatment for VCID. Resveratrol (RSV) is considered an antioxidant; however, our group has observed pleiotropic effects in stroke paradigms, suggesting more effects may contribute to mechanistic changes beyond antioxidative properties. The main goal of this study was to investigate if administering RSV twice a week could alleviate cognitive declines following the induction of a VCID model. Additionally, our aim was to further describe whether this treatment regimen could decrease cell death in brain areas vulnerable to changes in cerebral blood flow, such as the hippocampus and medial septum. We hypothesized RSV treatments in a mouse model of gradual cerebral hypoperfusion protect against cognitive impairment. We utilized gradual bilateral common carotid artery stenosis (GBCCAS) via the surgical implantation of ameroid constrictor devices. RSV treatment was administered on the day of implantation and twice a week thereafter. Cerebral perfusion was measured by laser speckle contrast imaging, and cognitive functions, including the recognition memory, the spatial working memory, and associative learning, were assessed by novel object recognition (NOR), Y-maze testing, and contextual fear conditioning (CFC), respectively. RSV treatment did not alleviate cerebral perfusion deficits but mitigated cognitive deficits in CFC and NOR after GBCCAS. Despite these deficits, no hippocampal pathology was observed; however, cholinergic cell loss in the medial septum was significantly increased after GBCCAS. This cholinergic cell loss was mitigated by RSV. This study describes a novel mechanism by which chronic RSV treatments protect against a VCID-induced cognitive decline through the preservation of cholinergic cell viability to improve memory performance. Full article

Chlorpyrifos (CPF) biocide, exposure to which is mainly produced in the human population through diet, induces several neurotoxic effects. CPF single and repeated exposure induces memory and learning disorders, although the mechanisms that produce these outcomes are complex and not well understood. CPF treatment (single and repeated) of cholinergic septal SN56 cells induced an increase in phosphorylated-P38α levels that led to WNT/β-Catenin and NGF/P75^NTR/TrkA pathways disruption and cell death. These results provide new knowledge on the mechanisms that mediate CPF basal forebrain cholinergic neuronal loss induced by CPF single and repeated exposure and can help unravel the way through which this compound produces cognitive decline and develop efficient treatments against these effects. Full article

Background: While frontotemporal involvement is increasingly recognized in Amyotrophic lateral sclerosis (ALS), the degeneration of limbic networks remains poorly characterized, despite growing evidence of amnestic deficits, impaired emotional processing and deficits in social cognition. Methods: A prospective neuroimaging study was conducted with 204 individuals with ALS and 111 healthy controls. Patients were stratified for hexanucleotide expansion status in C9orf72. A deep-learning-based segmentation approach was implemented to segment the nucleus accumbens, hypothalamus, fornix, mammillary body, basal forebrain and septal nuclei. The cortical, subcortical and white matter components of the Papez circuit were also systematically evaluated. Results: Hexanucleotide repeat expansion carriers exhibited bilateral amygdala, hypothalamus and nucleus accumbens atrophy, and C9orf72 negative patients showed bilateral basal forebrain volume reductions compared to controls. Both patient groups showed left rostral anterior cingulate atrophy, left entorhinal cortex thinning and cingulum and fornix alterations, irrespective of the genotype. Fornix, cingulum, posterior cingulate, nucleus accumbens, amygdala and hypothalamus degeneration was more marked in C9orf72-positive ALS patients. Conclusions: Our results highlighted that mesial temporal and parasagittal subcortical degeneration is not unique to C9orf72 carriers. Our radiological findings were consistent with neuropsychological observations and highlighted the importance of comprehensive neuropsychological testing in ALS, irrespective of the underlying genotype. Full article

Binge alcohol consumption during adolescence can produce lasting deficits in learning and memory while also increasing the susceptibility to substance use disorders. The adolescent intermittent ethanol (AIE) rodent model mimics human adolescent binge drinking and has identified the nucleus basalis magnocellularis (NbM) as a key site of pathology. The NbM is a critical regulator of prefrontal cortical (PFC) cholinergic function and attention. The cholinergic phenotype is controlled pro/mature neurotrophin receptor activation. We sought to determine if p75NTR activity contributes to the loss of cholinergic phenotype in AIE by using a p75NTR modulator (LM11A-31) to inhibit prodegenerative signaling during ethanol exposure. Male and female rats underwent 5 g/kg ethanol (AIE) or water (CON) exposure following 2-day-on 2-day-off cycles from postnatal day 25–57. A subset of these groups also received a protective dose of LM11A-31 (50 mg/kg) during adolescence. Rats were trained on a sustained attention task (SAT) and behaviorally relevant acetylcholine (ACh) activity was recorded in the PFC with a fluorescent indicator (AChGRAB 3.0). AIE produced learning deficits on the SAT, which were spared with LM11A-31. In addition, PFC ACh activity was blunted by AIE, which LM11A-31 corrected. Investigation of NbM ChAT+ and TrkA+ neuronal expression found that AIE led to a reduction of ChAT+TrkA+ neurons, which again LM11A-31 protected. Taken together, these findings demonstrate the p75NTR activity during AIE treatment is a key regulator of cholinergic degeneration. Full article

Sleep disruption is a frequent problem of advancing age, often accompanied by low-grade chronic central and peripheral inflammation. We examined whether chronic neuroinflammation in the preoptic and basal forebrain area (POA-BF), a critical sleep–wake regulatory structure, contributes to this disruption. We developed a targeted viral vector designed to overexpress tumor necrosis factor-alpha (TNFα), specifically in astrocytes (AAV5-GFAP-TNFα-mCherry), and injected it into the POA of young mice to induce heightened neuroinflammation within the POA-BF. Compared to the control (treated with AAV5-GFAP-mCherry), mice with astrocytic TNFα overproduction within the POA-BF exhibited signs of increased microglia activation, indicating a heightened local inflammatory milieu. These mice also exhibited aging-like changes in sleep–wake organization and physical performance, including (a) impaired sleep–wake functions characterized by disruptions in sleep and waking during light and dark phases, respectively, and a reduced ability to compensate for sleep loss; (b) dysfunctional VLPO sleep-active neurons, indicated by fewer neurons expressing c-fos after suvorexant-induced sleep; and (c) compromised physical performance as demonstrated by a decline in grip strength. These findings suggest that inflammation-induced dysfunction of sleep- and wake-regulatory mechanisms within the POA-BF may be a critical component of sleep–wake disturbances in aging. Full article