RESUMO
BACKGROUND: The cholinergic neurotransmitter system is crucial to cognitive function, with the basal forebrain (BF) being particularly susceptible to Alzheimer's disease (AD) pathology. However, the interaction of white matter hyperintensities (WMH) in cholinergic pathways and BF atrophy without amyloid pathology remains poorly understood. METHODS: We enrolled patients who underwent neuropsychological tests, magnetic resonance imaging, and 18F-florbetaben positron emission tomography due to cognitive impairment at the teaching university hospital from 2015 to 2022. Among these, we selected patients with negative amyloid scans and additionally excluded those with Parkinson's dementia that may be accompanied by BF atrophy. The WMH burden of cholinergic pathways was quantified by the Cholinergic Pathways Hyperintensities Scale (CHIPS) score, and categorized into tertile groups because the CHIPS score did not meet normal distribution. Segmentation of the BF on volumetric T1-weighted MRI was performed using FreeSurfer, then was normalized for total intracranial volume. Multivariable regression analysis was performed to investigate the association between BF volumes and CHIPS scores. RESULTS: A total of 187 patients were enrolled. The median CHIPS score was 12 [IQR 5.0; 24.0]. The BF volume of the highest CHIPS tertile group (mean ± SD, 3.51 ± 0.49, CHIPSt3) was significantly decreased than those of the lower CHIPS tertile groups (3.75 ± 0.53, CHIPSt2; 3.83 ± 0.53, CHIPSt1; P = 0.02). In the univariable regression analysis, factors showing significant associations with the BF volume were the CHIPSt3 group, age, female, education, diabetes mellitus, smoking, previous stroke history, periventricular WMH, and cerebral microbleeds. In multivariable regression analysis, the CHIPSt3 group (standardized beta [ßstd] = -0.25, P = 0.01), female (ßstd = 0.20, P = 0.04), and diabetes mellitus (ßstd = -0.22, P < 0.01) showed a significant association with the BF volume. Sensitivity analyses showed a negative correlation between CHIPS score and normalized BF volume, regardless of WMH severity. CONCLUSIONS: We identified a significant correlation between strategic WMH burden in the cholinergic pathway and BF atrophy independently of amyloid positivity and WMH severity. These results suggest a mechanism of cholinergic neuronal loss through the dying-back phenomenon and provide a rationale that strategic WMH assessment may help identify target groups that may benefit from acetylcholinesterase inhibitor treatment.
Assuntos
Prosencéfalo Basal , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Substância Branca , Humanos , Feminino , Masculino , Idoso , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Prosencéfalo Basal/diagnóstico por imagem , Prosencéfalo Basal/patologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Disfunção Cognitiva/metabolismo , Atrofia/patologia , Idoso de 80 Anos ou maisRESUMO
Humans and other animals readily transition from externally to internally focused attention, and these transitions are accompanied by activation of the default mode network (DMN). The DMN was considered a cortical network, yet recent evidence suggests subcortical structures are also involved. We investigated the role of ventral pallidum (VP) and mediodorsal thalamus (MD) in DMN regulation in tree shrew, a close relative of primates. Electrophysiology and deep learning-based classification of behavioral states revealed gamma oscillations in VP and MD coordinated with gamma in anterior cingulate (AC) cortex during DMN states. Cross-frequency coupling between gamma and delta oscillations was higher during DMN than other behaviors, underscoring the engagement of MD, VP and AC. Our findings highlight the importance of VP and MD in DMN regulation, extend homologies in DMN regulation among mammals, and underline the importance of thalamus and basal forebrain to the regulation of DMN.
Assuntos
Prosencéfalo Basal , Rede de Modo Padrão , Animais , Rede de Modo Padrão/fisiologia , Prosencéfalo Basal/fisiologia , Tupaiidae/fisiologia , Masculino , Tálamo/fisiologia , Giro do Cíngulo/fisiologia , Feminino , Núcleo Mediodorsal do Tálamo/fisiologiaRESUMO
The regulation of circadian rhythms and the sleep-wake states involves in multiple neural circuits. The suprachiasmatic nucleus (SCN) is a circadian pacemaker that controls the rhythmic oscillation of mammalian behaviors. The basal forebrain (BF) is a critical brain region of sleep-wake regulation, which is the downstream of the SCN. Retrograde tracing of cholera toxin subunit B showed a direct projection from the SCN to the horizontal limbs of diagonal band (HDB), a subregion of the BF. However, the underlying function of the SCN-HDB pathway remains poorly understood. Herein, activation of this pathway significantly increased non-rapid eye movement (NREM) sleep during the dark phase by using optogenetic recordings. Moreover, activation of this pathway significantly induced NREM sleep during the dark phase for first 4 h by using chemogenetic methods. Taken together, these findings reveal that the SCN-HDB pathway participates in NREM sleep regulation and provides direct evidence of a novel SCN-related pathway involved in sleep-wake states regulation.
Assuntos
Vias Eferentes , Optogenética , Núcleo Supraquiasmático , Animais , Núcleo Supraquiasmático/fisiologia , Masculino , Camundongos , Vias Eferentes/fisiologia , Camundongos Endogâmicos C57BL , Fases do Sono/fisiologia , Prosencéfalo Basal/fisiologia , Ritmo Circadiano/fisiologia , EletroencefalografiaRESUMO
BACKGROUND AND OBJECTIVES: In early Alzheimer disease (AD), ß-amyloid (Aß) deposition is associated with volume loss in the basal forebrain (BF) and cognitive decline. However, the extent to which Aß-related BF atrophy manifests as cognitive decline is not understood. This study sought to characterize the relationship between BF atrophy and the decline in memory and attention in patients with early AD. METHODS: Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study who completed Aß-PET imaging and repeated MRI and cognitive assessments were included. At baseline, participants were classified based on their clinical dementia stage and Aß status, yielding groups that were cognitively unimpaired (CU) Aß-, CU Aß+, and mild cognitive impairment (MCI) Aß+. Linear mixed-effects models were used to assess changes in volumetric measures of BF subregions and the hippocampus and changes in AIBL memory and attention composite scores for each group compared with CU Aß- participants. Associations between Aß burden, brain atrophy, and cognitive decline were evaluated and explored further using mediation analyses. RESULTS: The cohort included 476 participants (72.6 ± 5.9 years, 55.0% female) with longitudinal data from a median follow-up period of 6.1 years. Compared with the CU Aß- group (n = 308), both CU Aß+ (n = 107) and MCI Aß+ (n = 61) adults showed faster decline in BF and hippocampal volumes and in memory and attention (Cohen d = 0.73-1.74). Rates of atrophy in BF subregions and the hippocampus correlated with cognitive decline, and each individually mediated the impact of Aß burden on memory and attention decline. When all mediators were considered simultaneously, hippocampal atrophy primarily influenced the effect of Aß burden on memory decline (ß [SE] = -0.139 [0.032], proportion mediated [PM] = 28.0%) while the atrophy of the posterior nucleus basalis of Meynert in the BF (ß [SE] = -0.068 [0.029], PM = 13.1%) and hippocampus (ß [SE] = -0.121 [0.033], PM = 23.4%) distinctively influenced Aß-related attention decline. DISCUSSION: These findings highlight the significant role of BF atrophy in the complex pathway linking Aß to cognitive impairment in early stages of AD. Volumetric assessment of BF subregions could be essential in elucidating the relationships between the brain structure and behavior in AD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Atrofia , Prosencéfalo Basal , Disfunção Cognitiva , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Humanos , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/complicações , Feminino , Masculino , Atrofia/patologia , Idoso , Disfunção Cognitiva/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Peptídeos beta-Amiloides/metabolismo , Prosencéfalo Basal/patologia , Prosencéfalo Basal/diagnóstico por imagem , Idoso de 80 Anos ou mais , Hipocampo/patologia , Hipocampo/diagnóstico por imagem , Testes NeuropsicológicosRESUMO
Parvalbumin (PV)-expressing GABAergic neurons of the basal forebrain (BFPVNs) were proposed to serve as a rapid and transient arousal system, yet their exact role in awake behaviors remains unclear. We performed bulk calcium measurements and electrophysiology with optogenetic tagging from the horizontal limb of the diagonal band of Broca (HDB) while male mice were performing an associative learning task. BFPVNs responded with a distinctive, phasic activation to punishment, but showed slower and delayed responses to reward and outcome-predicting stimuli. Optogenetic inhibition during punishment impaired the formation of cue-outcome associations, suggesting a causal role of BFPVNs in associative learning. BFPVNs received strong inputs from the hypothalamus, the septal complex and the median raphe region, while they synapsed on diverse cell types in key limbic structures, where they broadcasted information about aversive stimuli. We propose that the arousing effect of BFPVNs is recruited by aversive stimuli to serve crucial associative learning functions.
Assuntos
Prosencéfalo Basal , Neurônios GABAérgicos , Optogenética , Parvalbuminas , Animais , Parvalbuminas/metabolismo , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiologia , Masculino , Camundongos , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Recompensa , Punição , Camundongos Endogâmicos C57BL , Aprendizagem/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Aprendizagem por Associação/fisiologiaRESUMO
Predictive learning can engage a selective form of cognitive control that biases choice between actions based on information about future outcomes that the learning provides. This influence has been hypothesized to depend on a feedback circuit in the brain through which the basal ganglia modulate activity in the prefrontal cortex; however, direct evidence for this functional circuit has proven elusive. Here, using an animal model of cognitive control, we found that the influence of predictive learning on decision making is mediated by an inhibitory feedback circuit linking the medial ventral pallidum and the mediodorsal thalamus, the activation of which causes disinhibition of the orbitofrontal cortex via reduced activation of inhibitory parvalbumin interneurons during choice. Thus, we found that, for this function, the mediodorsal thalamus serves as a pallidal-cortical relay through which predictive learning controls action selection, which has important implications for understanding cognitive control and its vicissitudes in various psychiatric disorders and addiction.
Assuntos
Cognição , Animais , Cognição/fisiologia , Masculino , Córtex Pré-Frontal/fisiologia , Prosencéfalo Basal/fisiologia , Vias Neurais/fisiologia , Tálamo/fisiologia , Tomada de Decisões/fisiologia , Aprendizagem/fisiologia , Camundongos , Interneurônios/fisiologiaRESUMO
The full mechanism of action of propofol, a commonly administered intravenous anesthetic drug in clinical practice, remains elusive. The focus of this study was the role of GABAergic neurons which are the main neuron group in the ventral pallidum (VP) closely associated with anesthetic effects in propofol anesthesia. The activity of VP GABAergic neurons following propofol anesthesia in Vgat-Cre mice was observed via detecting c-Fos immunoreactivity by immunofluorescence and western blotting. Subsequently, chemogenetic techniques were employed in Vgat-Cre mice to regulate the activity of VP GABAergic neurons. The role of VP GABAergic neurons in generating the effects of general anesthesia induced by intravenous propofol was further explored through behavioral tests of the righting reflex. The results revealed that c-Fos expression in VP GABAergic neurons in Vgat-Cre mice dramatically decreased after propofol injection. Further studies demonstrated that chemogenetic activation of VP GABAergic neurons during propofol anesthesia shortened the duration of anesthesia and promoted wakefulness. Conversely, the inhibition of VP GABAergic neurons extended the duration of anesthesia and facilitated the effects of anesthesia. The results obtained in this study suggested that regulating the activity of GABAergic neurons in the ventral pallidum altered the effect of propofol on general anesthesia.
Assuntos
Anestesia Geral , Anestésicos Intravenosos , Prosencéfalo Basal , Neurônios GABAérgicos , Propofol , Propofol/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Animais , Prosencéfalo Basal/efeitos dos fármacos , Anestésicos Intravenosos/farmacologia , Anestesia Geral/métodos , Camundongos , Masculino , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Reflexo de Endireitamento/efeitos dos fármacos , Reflexo de Endireitamento/fisiologia , Vigília/efeitos dos fármacos , Vigília/fisiologia , Camundongos Endogâmicos C57BL , Proteínas Vesiculares de Transporte de Aminoácidos InibidoresRESUMO
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.
Assuntos
Envelhecimento , Astrócitos , Prosencéfalo Basal , Área Pré-Óptica , Sono , Fator de Necrose Tumoral alfa , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Envelhecimento/metabolismo , Área Pré-Óptica/metabolismo , Camundongos , Fator de Necrose Tumoral alfa/metabolismo , Sono/fisiologia , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/patologia , Vigília , Masculino , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neurônios/patologia , Transtornos do Sono-Vigília/metabolismo , Transtornos do Sono-Vigília/patologiaRESUMO
The ventral pallidum (VP) receives its primary inputs from the nucleus accumbens (NAC) and the basolateral amygdala (BLA). We demonstrated recently that in the VP, the D2 DA receptor (D2R) agonist quinpirole dose-dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. In the VP, D2R can be found both on NAC and BLA terminals. According to our hypothesis, quinpirole microinjected into the VP can facilitate memory consolidation via modulation of synaptic plasticity on NAC and/or BLA terminals. The effect of intra-VP quinpirole on BLA-VP and NAC shell-VP synapses was investigated via a high frequency stimulation (HFS) protocol. Quinpirole was administered in three doses into the VP of male Sprague-Dawley rats after HFS; controls received vehicle. To examine whether an interaction between the NAC shell and the BLA at the level of the VP was involved, tetrodotoxin (TTX) was microinjected into one of the nuclei while stimulating the other nucleus. Our results showed that quinpirole dose-dependently modulates BLA-VP and NAC shell-VP synapses, similar to those observed in inhibitory avoidance and spatial learning, respectively. The lower dose inhibits BLA inputs, while the larger doses facilitates NAC shell inputs. The experiments with TTX demonstrates that the two nuclei do not influence each others' evoked responses in the VP. Power spectral density analysis demonstrated that independent from the synaptic facilitation, intra-VP quinpirole increases the amplitude of gamma frequency band after NAC HFS, and BLA tonically suppresses the NAC's HFS-induced gamma facilitation. In contrast, HFS of the BLA results in a delayed, transient increase in the amplitude of the gamma frequency band correlating with the LTP of the P1 component of the VP response to BLA stimulation. Furthermore, our results demonstrate that the BLA plays a prominent role in the generation of the delta oscillations: HFS of the BLA leads to a gradually increasing delta frequency band facilitation over time, while BLA inhibition blocks the NAC's HFS induced strong delta facilitation. These findings demonstrate that there is a complex interaction between the NAC shell region and the VP, as well as the BLA and the VP, and support the important role of VP D2Rs in the regulation of limbic information flow.
Assuntos
Prosencéfalo Basal , Agonistas de Dopamina , Relação Dose-Resposta a Droga , Microinjeções , Quimpirol , Ratos Sprague-Dawley , Receptores de Dopamina D2 , Animais , Quimpirol/farmacologia , Masculino , Prosencéfalo Basal/efeitos dos fármacos , Prosencéfalo Basal/fisiologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/efeitos dos fármacos , Ratos , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/fisiologia , Estimulação Elétrica , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/fisiologiaRESUMO
We aimed to study atrophy and glucose metabolism of the cholinergic basal forebrain in non-demented mutation carriers for autosomal dominant Alzheimer's disease (ADAD). We determined the level of evidence for or against atrophy and impaired metabolism of the basal forebrain in 167 non-demented carriers of the Colombian PSEN1 E280A mutation and 75 age- and sex-matched non-mutation carriers of the same kindred using a Bayesian analysis framework. We analyzed baseline MRI, amyloid PET, and FDG-PET scans of the Alzheimer's Prevention Initiative ADAD Colombia Trial. We found moderate evidence against an association of carrier status with basal forebrain volume (Bayes factor (BF10) = 0.182). We found moderate evidence against a difference of basal forebrain metabolism (BF10 = 0.167). There was only inconclusive evidence for an association between basal forebrain volume and delayed memory and attention (BF10 = 0.884 and 0.184, respectively), and between basal forebrain volume and global amyloid load (BF10 = 2.1). Our results distinguish PSEN1 E280A mutation carriers from sporadic AD cases in which cholinergic involvement of the basal forebrain is already detectable in the preclinical and prodromal stages. This indicates an important difference between ADAD and sporadic AD in terms of pathogenesis and potential treatment targets.
Assuntos
Doença de Alzheimer , Prosencéfalo Basal , Heterozigoto , Mutação , Tomografia por Emissão de Pósitrons , Presenilina-1 , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Feminino , Masculino , Presenilina-1/genética , Pessoa de Meia-Idade , Colômbia , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/patologia , Prosencéfalo Basal/diagnóstico por imagem , Imageamento por Ressonância Magnética , Adulto , Atrofia , Idoso , Teorema de BayesRESUMO
Elucidating the neural basis of fear allows for more effective treatments for maladaptive fear often observed in psychiatric disorders. Although the basal forebrain (BF) has an essential role in fear learning, its function in fear expression and the underlying neuronal and circuit substrates are much less understood. Here we report that BF glutamatergic neurons are robustly activated by social stimulus following social fear conditioning in male mice. And cell-type-specific inhibition of those excitatory neurons largely reduces social fear expression. At the circuit level, BF glutamatergic neurons make functional contacts with the lateral habenula (LHb) neurons and these connections are potentiated in conditioned mice. Moreover, optogenetic inhibition of BF-LHb glutamatergic pathway significantly reduces social fear responses. These data unravel an important function of the BF in fear expression via its glutamatergic projection onto the LHb, and suggest that selective targeting BF-LHb excitatory circuitry could alleviate maladaptive fear in relevant disorders.
Assuntos
Prosencéfalo Basal , Medo , Habenula , Neurônios , Animais , Habenula/fisiologia , Masculino , Medo/fisiologia , Prosencéfalo Basal/fisiologia , Prosencéfalo Basal/metabolismo , Camundongos , Neurônios/fisiologia , Neurônios/metabolismo , Optogenética , Camundongos Endogâmicos C57BL , Comportamento Social , Comportamento Animal/fisiologia , Vias Neurais/fisiologia , Ácido Glutâmico/metabolismo , Condicionamento Clássico/fisiologiaRESUMO
Vasopressin (AVP) regulates various social behaviors, often in sex-specific ways, including social play behavior, a rewarding behavior displayed primarily by juveniles. Here, we examined whether and how AVP acting in the brain's reward system regulates social play behavior in juvenile rats. Specifically, we focused on AVP signaling in the ventral pallidum (VP), a brain region that is a part of the reward system. First, we examined the organization of the VP-AVP system in juvenile rats and found sex differences, with higher density of both AVP-immunoreactive fibers and AVP V1a receptor (V1aR) binding in males compared to females while females show a greater number of V1aR-expressing cells compared to males. We further found that, in both sexes, V1aR-expressing cells co-express a GABA marker to a much greater extent (approx. 10 times) than a marker for glutamate. Next, we examined the functional involvement of V1aR-expressing VP cells in social play behavior. We found that exposure to social play enhanced the proportion of activated V1aR-expressing VP cells in males only. Finally, we showed that infusion of a specific V1aR antagonist into the VP increased social play behaviors in juvenile male rats while decreasing these behaviors in juvenile female rats. Overall, these findings reveal structural and functional sex differences in the AVP-V1aR system in the VP that are associated with the sex-specific regulation of social play behavior.
Assuntos
Prosencéfalo Basal , Receptores de Vasopressinas , Caracteres Sexuais , Comportamento Social , Vasopressinas , Animais , Masculino , Feminino , Ratos , Receptores de Vasopressinas/metabolismo , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiologia , Vasopressinas/metabolismo , Jogos e Brinquedos , Arginina Vasopressina/metabolismo , Comportamento Animal/fisiologia , Ratos Long-Evans , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologiaRESUMO
Cholinergic neurons of the basal forebrain represent the main source of cholinergic innervation of large parts of the neocortex and are involved in adults in the modulation of attention, memory, and arousal. During the first postnatal days, they play a crucial role in the development of cortical neurons and cortical cytoarchitecture. However, their characteristics, during this period have not been studied. To understand how they can fulfill this role, we investigated the morphological and electrophysiological maturation of cholinergic neurons of the substantia innominata-nucleus basalis of Meynert (SI/NBM) complex in the perinatal period in mice. We show that cholinergic neurons, whether or not they express gamma-aminobutyric acid (GABA) as a cotransmitter, are already functional at Embryonic Day 18. Until the end of the first postnatal week, they constitute a single population of neurons with a well developed dendritic tree, a spontaneous activity including bursting periods, and a short-latency response to depolarizations (early-firing). They are excited by both their GABAergic and glutamatergic afferents. During the second postnatal week, a second, less excitable, neuronal population emerges, with a longer delay response to depolarizations (late-firing), together with the hyperpolarizing action of GABAA receptor-mediated currents. This classification into early-firing (40%) and late-firing (60%) neurons is again independent of the coexpression of GABAergic markers. These results strongly suggest that during the first postnatal week, the specific properties of developing SI/NBM cholinergic neurons allow them to spontaneously release acetylcholine (ACh), or ACh and GABA, into the developing cortex.
Assuntos
Prosencéfalo Basal , Neurônios Colinérgicos , Ácido gama-Aminobutírico , Animais , Neurônios Colinérgicos/fisiologia , Neurônios Colinérgicos/metabolismo , Ácido gama-Aminobutírico/metabolismo , Prosencéfalo Basal/fisiologia , Prosencéfalo Basal/metabolismo , Animais Recém-Nascidos , Camundongos Endogâmicos C57BL , Feminino , Núcleo Basal de Meynert/fisiologia , Núcleo Basal de Meynert/metabolismo , Substância Inominada/fisiologia , Substância Inominada/metabolismo , Camundongos , Receptores de GABA-A/metabolismo , Potenciais de Ação/fisiologia , Técnicas de Patch-Clamp , Ácido Glutâmico/metabolismoRESUMO
Dysfunction of subcortical D2-like dopamine receptors (D2Rs) can lead to positive symptoms of schizophrenia, and their analog, the increased locomotor activity in schizophrenia model MAM-E17 rats. The ventral pallidum (VP) is a limbic structure containing D2Rs. The D2R antagonist sulpiride is a widespread antipsychotic drug, which can alleviate positive symptoms in human patients. However, it is still not known how sulpiride can influence positive symptoms via VP D2Rs. We hypothesize that the microinjection of sulpiride into the VP can normalize hyperactivity in MAM-E17 rats. In addition, recently, we showed that the microinjection of sulpirid into the VP induces place preference in neurotypical rats. Thus, we aimed to test whether intra-VP sulpiride can also have a rewarding effect in MAM-E17 rats. Therefore, open field-based conditioned place preference (CPP) test was applied in neurotypical (SAL-E17) and MAM-E17 schizophrenia model rats to test locomotor activity and the potential locomotor-reducing and rewarding effects of sulpiride. Sulpiride was microinjected bilaterally in three different doses into the VP, and the controls received only vehicle. The results of the present study demonstrated that the increased locomotor activity of the MAM-E17 rats was caused by habituation disturbance. Accordingly, larger doses of sulpiride in the VP reduce the positive symptom-analog habituation disturbance of the MAM-E17 animals. Furthermore, we showed that the largest dose of sulpiride administered into the VP induced CPP in the SAL-E17 animals but not in the MAM-E17 animals. These findings revealed that VP D2Rs play an important role in the formation of positive symptom-like habituation disturbances in MAM-E17 rats.
Assuntos
Antipsicóticos , Prosencéfalo Basal , Modelos Animais de Doenças , Habituação Psicofisiológica , Microinjeções , Esquizofrenia , Sulpirida , Animais , Sulpirida/farmacologia , Sulpirida/administração & dosagem , Esquizofrenia/tratamento farmacológico , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacologia , Ratos , Prosencéfalo Basal/efeitos dos fármacos , Masculino , Habituação Psicofisiológica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Receptores de Dopamina D2/metabolismoRESUMO
Here, we describe a group of basal forebrain (BF) neurons expressing neuronal Per-Arnt-Sim (PAS) domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1+ neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1+ neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1+ neurons was high, five to six times that of neighboring cholinergic, parvalbumin, or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1+ neurons to brain regions involved in sleep-wake control, motivated behaviors, and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area, and olfactory bulb. Chemogenetic activation of BF Npas1+ neurons in the light period increased the amount of wakefulness and the latency to sleep for 2 to 3 h, due to an increase in long wake bouts and short NREM sleep bouts. NREM slow-wave and sigma power, as well as sleep spindle density, amplitude, and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1+ neurons in stress responsiveness, the anatomical projections of BF Npas1+ neurons and the effect of activating them suggest a possible role for BF Npas1+ neurons in motivationally driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia, and other neuropsychiatric conditions involving BF.
Assuntos
Prosencéfalo Basal , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Neurônios GABAérgicos , Vigília , Animais , Masculino , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Camundongos Transgênicos , Sono/fisiologia , Vigília/fisiologiaRESUMO
The ventral pallidum is a prominent structure within the basal ganglia, regulating reward and motivational processes. Positioned at the interface between motor and limbic structures, its function is crucial to the development and maintenance of substance use disorders. Chronic drug use induces neuroplastic events in this structure, leading to long-term changes in VP neuronal activity and synaptic communication. Moreover, different neuronal populations within the VP drive drug-seeking behavior in opposite directions. This review explores the role of the VP as a hub for reward, motivation, and aversion, establishing it as an important contributor to the pathophysiology of substance use disorders.
Assuntos
Prosencéfalo Basal , Transtornos Relacionados ao Uso de Substâncias , Humanos , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/patologia , Animais , Prosencéfalo Basal/fisiologia , Recompensa , Vias Neurais/fisiopatologia , Vias Neurais/fisiologiaRESUMO
The ventral pallidum (VP) contains GABA and glutamate neurons projecting to ventral tegmental area (VTA) whose stimulation drives approach and avoidance, respectively. Yet little is known about the mechanisms by which VP cell types shape VTA activity and drive behavior. Here, we found that both VP GABA and glutamate neurons were activated during approach to reward or by delivery of an aversive stimulus. Stimulation of VP GABA neurons inhibited VTA GABA, but activated dopamine and glutamate neurons. Remarkably, stimulation-evoked activation was behavior-contingent such that VTA recruitment was inhibited when evoked by the subject's own action. Conversely, VP glutamate neurons activated VTA GABA, as well as dopamine and glutamate neurons, despite driving aversion. However, VP glutamate neurons evoked dopamine in aversion-associated ventromedial nucleus accumbens (NAc), but reduced dopamine release in reward-associated dorsomedial NAc. These findings show how heterogeneous VP projections to VTA can be engaged to shape approach and avoidance behaviors.
Assuntos
Aprendizagem da Esquiva , Prosencéfalo Basal , Neurônios GABAérgicos , Ácido Glutâmico , Recompensa , Área Tegmentar Ventral , Área Tegmentar Ventral/fisiologia , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/citologia , Animais , Ácido Glutâmico/metabolismo , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiologia , Masculino , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Aprendizagem da Esquiva/fisiologia , Camundongos , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/citologia , Núcleo Accumbens/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Ácido gama-Aminobutírico/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/fisiologia , Camundongos Endogâmicos C57BL , Comportamento Animal/fisiologiaRESUMO
Cortical acetylcholine (ACh) release has been linked to various cognitive functions, including perceptual learning. We have previously shown that cortical cholinergic innervation is necessary for accurate sound localization in ferrets, as well as for their ability to adapt with training to altered spatial cues. To explore whether these behavioral deficits are associated with changes in the response properties of cortical neurons, we recorded neural activity in the primary auditory cortex (A1) of anesthetized ferrets in which cholinergic inputs had been reduced by making bilateral injections of the immunotoxin ME20.4-SAP in the nucleus basalis (NB) prior to training the animals. The pattern of spontaneous activity of A1 units recorded in the ferrets with cholinergic lesions (NB ACh-) was similar to that in controls, although the proportion of burst-type units was significantly lower. Depletion of ACh also resulted in more synchronous activity in A1. No changes in thresholds, frequency tuning or in the distribution of characteristic frequencies were found in these animals. When tested with normal acoustic inputs, the spatial sensitivity of A1 neurons in the NB ACh- ferrets and the distribution of their preferred interaural level differences also closely resembled those found in control animals, indicating that these properties had not been altered by sound localization training with one ear occluded. Simulating the animals' previous experience with a virtual earplug in one ear reduced the contralateral preference of A1 units in both groups, but caused azimuth sensitivity to change in slightly different ways, which may reflect the modest adaptation observed in the NB ACh- group. These results show that while ACh is required for behavioral adaptation to altered spatial cues, it is not required for maintenance of the spectral and spatial response properties of A1 neurons.
Assuntos
Estimulação Acústica , Córtex Auditivo , Prosencéfalo Basal , Furões , Animais , Córtex Auditivo/metabolismo , Córtex Auditivo/fisiopatologia , Prosencéfalo Basal/metabolismo , Localização de Som , Acetilcolina/metabolismo , Masculino , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/patologia , Vias Auditivas/fisiopatologia , Vias Auditivas/metabolismo , Feminino , Imunotoxinas/toxicidade , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/fisiopatologia , Núcleo Basal de Meynert/patologia , Neurônios/metabolismo , Limiar Auditivo , Adaptação Fisiológica , Comportamento AnimalRESUMO
Foraging decisions involve assessing potential risks and prioritizing food sources, which can be challenging when confronted with changing and conflicting circumstances. A crucial aspect of this decision-making process is the ability to actively overcome defensive reactions to threats and focus on achieving specific goals. The ventral pallidum (VP) and basolateral amygdala (BLA) are two brain regions that play key roles in regulating behavior motivated by either rewards or threats. However, it is unclear whether these regions are necessary in decision-making processes involving competing motivational drives during conflict. Our aim was to investigate the requirements of the VP and BLA for foraging choices in conflicts involving overcoming defensive responses. Here, we used a novel foraging task and pharmacological techniques to inactivate either the VP or BLA or to disconnect these brain regions before conducting a conflict test in male rats. Our findings showed that BLA is necessary for making risky choices during conflicts, whereas VP is necessary for invigorating the drive to obtain food, regardless of the presence of conflict. Importantly, our research revealed that the connection between VP and BLA is critical in controlling risky food-seeking choices during conflict situations. This study provides a new perspective on the collaborative function of VP and BLA in driving behavior, aimed at achieving goals in the face of dangers.