Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 175
Filtrar
1.
Sci Signal ; 17(855): eadn2616, 2024 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-39316663

RESUMEN

Basal forebrain cholinergic neurons (BFCNs) extend long projections to multiple regions in the brain to regulate cognitive functions. Degeneration of BFCNs is seen with aging, after brain injury, and in neurodegenerative disorders. An increase in the amount of the immature proform of nerve growth factor (proNGF) in the cerebral cortex results in retrograde degeneration of BFCNs through activation of proNGF receptor p75NTR. Here, we investigated the signaling cascades initiated at the axon terminal that mediate proNGF-induced retrograde degeneration. We found that local axonal protein synthesis and retrograde transport mediated proNGF-induced degeneration initiated from the axon terminal. Analysis of the nascent axonal proteome revealed that proNGF stimulation of axonal terminals triggered the synthesis of numerous proteins within the axon, and pathway analysis showed that amyloid precursor protein (APP) was a key upstream regulator in cultured BFCNs and in mice. Our findings reveal a functional role for APP in mediating BFCN axonal degeneration and cell death induced by proNGF.


Asunto(s)
Precursor de Proteína beta-Amiloide , Axones , Prosencéfalo Basal , Factor de Crecimiento Nervioso , Animales , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Axones/metabolismo , Axones/patología , Factor de Crecimiento Nervioso/metabolismo , Factor de Crecimiento Nervioso/genética , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/patología , Ratones , Receptores de Factor de Crecimiento Nervioso/metabolismo , Receptores de Factor de Crecimiento Nervioso/genética , Precursores de Proteínas/metabolismo , Precursores de Proteínas/genética , Neuronas Colinérgicas/metabolismo , Neuronas Colinérgicas/patología , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Ratones Endogámicos C57BL , Células Cultivadas , Transducción de Señal
2.
Nat Metab ; 6(9): 1775-1790, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39112722

RESUMEN

Feeding behaviour is influenced by two primary factors: homoeostatic needs driven by hunger and hedonic desires for pleasure even in the absence of hunger. While efficient homoeostatic feeding is vital for survival, excessive hedonic feeding can lead to adverse consequences such as obesity and metabolic dysregulations. However, the neurobiological mechanisms that orchestrate homoeostatic versus hedonic food consumption remain largely unknown. Here we show that GABAergic proenkephalin (Penk) neurons in the diagonal band of Broca (DBB) of male mice respond to food presentation. We further demonstrate that a subset of DBBPenk neurons that project to the paraventricular nucleus of the hypothalamus are preferentially activated upon food presentation during fasting periods and transmit a positive valence to facilitate feeding. On the other hand, a separate subset of DBBPenk neurons that project to the lateral hypothalamus are preferentially activated when detecting a high-fat high-sugar (HFHS) diet and transmit a negative valence to inhibit food consumption. Notably, when given free choice of chow and HFHS diets, mice with the whole DBBPenk population ablated exhibit reduced consumption of chow but increased intake of the HFHS diet, resulting in accelerated development of obesity and metabolic disturbances. Together, we identify a molecularly defined neural population in male mice that is crucial for the maintenance of energy balance by facilitating homoeostatic feeding while suppressing hedonic overeating.


Asunto(s)
Prosencéfalo Basal , Conducta Alimentaria , Animales , Masculino , Ratones , Conducta Alimentaria/fisiología , Prosencéfalo Basal/fisiología , Prosencéfalo Basal/metabolismo , Encefalinas/metabolismo , Ingestión de Alimentos/fisiología , Precursores de Proteínas/metabolismo , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Vías Nerviosas/fisiología , Obesidad/etiología , Neuronas/fisiología , Neuronas/metabolismo
3.
Pharmacol Biochem Behav ; 243: 173837, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39053857

RESUMEN

Rearing rats in environmental enrichment produces a protective effect when exposed to stimulants, as enriched rats display attenuated cocaine seeking during reinstatement. However, less is known about what changes in the brain are responsible for this protective effect. The current study investigated differences in Fos protein expression following reinstatement of cocaine seeking in differentially reared rats. Rats were reared in either enriched (EC) or impoverished (IC) conditions for 30 days, after which rats self-administered cocaine in 2-h sessions. Following self-administration, rats underwent extinction and cue-induced or cocaine-primed reinstatement of cocaine seeking, brains were extracted, and Fos immunohistochemistry was performed. IC rats sought cocaine significantly more than EC rats during cue-induced reinstatement, and cocaine seeking was positively correlated with Fos expression in the nucleus accumbens core and ventral pallidum. IC rats displayed greater Fos expression than EC rats in the accumbens and ventral pallidum, suggesting a role of these areas in the enrichment-induced protective effect.


Asunto(s)
Cocaína , Núcleo Accumbens , Ratas Sprague-Dawley , Autoadministración , Animales , Masculino , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Ratas , Cocaína/farmacología , Cocaína/administración & dosificación , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Extinción Psicológica/efectos de los fármacos
4.
Neuropeptides ; 107: 102449, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38908356

RESUMEN

Previous research has demonstrated that basal forebrain (BF) regulates arousal during propofol anesthesia. However, as the BF comprises cholinergic neurons alongside two other types of neurons, the specific role of cholinergic neurons has not been definitively elucidated. In our study, calcium signal imaging was utilized to monitor the real-time activities of cholinergic neurons in the BF during propofol anesthesia. Additionally, we selectively stimulated these neurons to investigate EEG and behavioral responses during propofol anesthesia. Furthermore, we specifically lesioned cholinergic neurons in the BF to investigate the sensitivity to propofol and the induction time. The results revealed that propofol suppressed calcium signals of cholinergic neurons within the BF following intraperitoneal injection. Notably, upon recovery of the righting reflex, the calcium signals partially recovered. Spectral analysis of the EEG elucidated that optical stimulation of cholinergic neurons led to a decrease in δ power underlie propofol anesthesia. Conversely, depletion of cholinergic neurons in the BF enhanced sensitivity to propofol and shortened the induction time. These findings clarify the role of cholinergic neurons in the anesthesia-arousal process, as well as the depth and the sensitivity of propofol anesthesia.


Asunto(s)
Anestésicos Intravenosos , Prosencéfalo Basal , Neuronas Colinérgicas , Propofol , Propofol/farmacología , Neuronas Colinérgicas/efectos de los fármacos , Neuronas Colinérgicas/metabolismo , Animales , Prosencéfalo Basal/efectos de los fármacos , Prosencéfalo Basal/metabolismo , Masculino , Anestésicos Intravenosos/farmacología , Nivel de Alerta/efectos de los fármacos , Nivel de Alerta/fisiología , Electroencefalografía , Anestesia , Ratones
5.
Cells ; 13(11)2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38891027

RESUMEN

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.


Asunto(s)
Envejecimiento , Astrocitos , Prosencéfalo Basal , Área Preóptica , Sueño , Factor de Necrosis Tumoral alfa , Animales , Astrocitos/metabolismo , Astrocitos/patología , Envejecimiento/metabolismo , Área Preóptica/metabolismo , Ratones , Factor de Necrosis Tumoral alfa/metabolismo , Sueño/fisiología , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/patología , Vigilia , Masculino , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neuronas/patología , Trastornos del Sueño-Vigilia/metabolismo , Trastornos del Sueño-Vigilia/patología
6.
Nat Commun ; 15(1): 4768, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38849336

RESUMEN

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.


Asunto(s)
Prosencéfalo Basal , Neuronas GABAérgicas , Optogenética , Parvalbúminas , Animales , Parvalbúminas/metabolismo , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiología , Masculino , Ratones , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/fisiología , Recompensa , Castigo , Ratones Endogámicos C57BL , Aprendizaje/fisiología , Neuronas/metabolismo , Neuronas/fisiología , Aprendizaje por Asociación/fisiología
7.
Hear Res ; 447: 109025, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38733712

RESUMEN

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.


Asunto(s)
Estimulación Acústica , Corteza Auditiva , Prosencéfalo Basal , Hurones , Animales , Corteza Auditiva/metabolismo , Corteza Auditiva/fisiopatología , Prosencéfalo Basal/metabolismo , Localización de Sonidos , Acetilcolina/metabolismo , Masculino , Neuronas Colinérgicas/metabolismo , Neuronas Colinérgicas/patología , Vías Auditivas/fisiopatología , Vías Auditivas/metabolismo , Femenino , Inmunotoxinas/toxicidad , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/fisiopatología , Núcleo Basal de Meynert/patología , Neuronas/metabolismo , Umbral Auditivo , Adaptación Fisiológica , Conducta Animal
8.
Neuropsychopharmacology ; 49(11): 1700-1710, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38714787

RESUMEN

Relapse is a major challenge in the treatment of drug addiction, and exercise has been shown to decrease relapse to drug seeking in animal models. However, the neural circuitry mechanisms by which exercise inhibits morphine relapse remain unclear. In this study, we report that 4-week treadmill training prevented morphine conditioned place preference (CPP) expression during abstinence by acting through the nucleus accumbens (NAc)-ventral pallidum (VP) pathway. We found that neuronal excitability was reduced in D2-dopamine receptor-expressing medium spiny neurons (D2-MSNs) following repeated exposure to morphine and forced abstinence. Enhancing the excitability of NAc D2-MSNs via treadmill training decreased the expression of morphine CPP. We also found that the effects of treadmill training were mediated by decreasing enkephalin levels and that restoring opioid modulation of GABA neurotransmission in the VP, which increased neurotransmitter release from NAc D2-MSNs to VP, decreased morphine CPP. Our findings suggest the inhibitory effect of exercise on morphine CPP is mediated by reversing morphine-induced neuroadaptations in the NAc-to-VP pathway.


Asunto(s)
Morfina , Núcleo Accumbens , Receptores de Dopamina D2 , Transmisión Sináptica , Ácido gamma-Aminobutírico , Animales , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Masculino , Morfina/farmacología , Receptores de Dopamina D2/metabolismo , Ratones , Ácido gamma-Aminobutírico/metabolismo , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Condicionamiento Físico Animal/fisiología , Condicionamiento Físico Animal/métodos , Ratones Endogámicos C57BL , Prosencéfalo Basal/efectos de los fármacos , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiología , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología
9.
Horm Behav ; 163: 105563, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38772158

RESUMEN

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.


Asunto(s)
Prosencéfalo Basal , Receptores de Vasopresinas , Caracteres Sexuales , Conducta Social , Vasopresinas , Animales , Masculino , Femenino , Ratas , Receptores de Vasopresinas/metabolismo , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiología , Vasopresinas/metabolismo , Juego e Implementos de Juego , Arginina Vasopresina/metabolismo , Conducta Animal/fisiología , Ratas Long-Evans , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología
10.
Proc Natl Acad Sci U S A ; 121(21): e2321410121, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38748575

RESUMEN

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.


Asunto(s)
Prosencéfalo Basal , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Neuronas GABAérgicas , Vigilia , Animales , Masculino , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/fisiología , Ratones Transgénicos , Sueño/fisiología , Vigilia/fisiología
11.
Sci Rep ; 14(1): 11268, 2024 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-38760448

RESUMEN

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.


Asunto(s)
Enfermedad de Alzheimer , Prosencéfalo Basal , Heterocigoto , Mutación , Tomografía de Emisión de Positrones , Presenilina-1 , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Femenino , Masculino , Presenilina-1/genética , Persona de Mediana Edad , Colombia , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/patología , Prosencéfalo Basal/diagnóstico por imagen , Imagen por Resonancia Magnética , Adulto , Atrofia , Anciano , Teorema de Bayes
12.
Nat Commun ; 15(1): 4233, 2024 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-38762463

RESUMEN

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.


Asunto(s)
Reacción de Prevención , Prosencéfalo Basal , Neuronas GABAérgicas , Ácido Glutámico , Recompensa , Área Tegmental Ventral , Área Tegmental Ventral/fisiología , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/citología , Animales , Ácido Glutámico/metabolismo , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiología , Masculino , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/fisiología , Reacción de Prevención/fisiología , Ratones , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/citología , Núcleo Accumbens/fisiología , Neuronas/metabolismo , Neuronas/fisiología , Ácido gamma-Aminobutírico/metabolismo , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/fisiología , Ratones Endogámicos C57BL , Conducta Animal/fisiología
13.
Nat Commun ; 15(1): 4013, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38740778

RESUMEN

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.


Asunto(s)
Prosencéfalo Basal , Miedo , Habénula , Neuronas , Animales , Habénula/fisiología , Masculino , Miedo/fisiología , Prosencéfalo Basal/fisiología , Prosencéfalo Basal/metabolismo , Ratones , Neuronas/fisiología , Neuronas/metabolismo , Optogenética , Ratones Endogámicos C57BL , Conducta Social , Conducta Animal/fisiología , Vías Nerviosas/fisiología , Ácido Glutámico/metabolismo , Condicionamiento Clásico/fisiología
14.
eNeuro ; 11(5)2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38755010

RESUMEN

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.


Asunto(s)
Prosencéfalo Basal , Neuronas Colinérgicas , Ácido gamma-Aminobutírico , Animales , Neuronas Colinérgicas/fisiología , Neuronas Colinérgicas/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Prosencéfalo Basal/fisiología , Prosencéfalo Basal/metabolismo , Animales Recién Nacidos , Ratones Endogámicos C57BL , Femenino , Núcleo Basal de Meynert/fisiología , Núcleo Basal de Meynert/metabolismo , Sustancia Innominada/fisiología , Sustancia Innominada/metabolismo , Ratones , Receptores de GABA-A/metabolismo , Potenciales de Acción/fisiología , Técnicas de Placa-Clamp , Ácido Glutámico/metabolismo
15.
J Alzheimers Dis ; 99(1): 145-159, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38640150

RESUMEN

Background: Degeneration of cholinergic basal forebrain (BF) neurons characterizes Alzheimer's disease (AD). However, what role the BF plays in the dynamics of AD pathophysiology has not been investigated precisely. Objective: To investigate the baseline and longitudinal roles of BF along with core neuropathologies in AD. Methods: In this retrospective cohort study, we enrolled 113 subjects (38 amyloid [Aß]-negative cognitively unimpaired, 6 Aß-positive cognitively unimpaired, 39 with prodromal AD, and 30 with AD dementia) who performed brain MRI for BF volume and cortical thickness, 18F-florbetaben PET for Aß, 18F-flortaucipir PET for tau, and detailed cognitive testing longitudinally. We investigated the baseline and longitudinal association of BF volume with Aß and tau standardized uptake value ratio and cognition. Results: Cross-sectionally, lower BF volume was not independently associated with higher cortical Aß, but it was associated with tau burden. Tau burden in the orbitofrontal, insular, lateral temporal, inferior temporo-occipital, and anterior cingulate cortices were associated with progressive BF atrophy. Lower BF volume was associated with faster Aß accumulation, mainly in the prefrontal, anterior temporal, cingulate, and medial occipital cortices. BF volume was associated with progressive decline in language and memory functions regardless of baseline Aß and tau burden. Conclusions: Tau deposition affected progressive BF atrophy, which in turn accelerated amyloid deposition, leading to a vicious cycle. Also, lower baseline BF volume independently predicted deterioration in cognitive function.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Prosencéfalo Basal , Cognición , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Masculino , Femenino , Anciano , Proteínas tau/metabolismo , Prosencéfalo Basal/patología , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/diagnóstico por imagen , Péptidos beta-Amiloides/metabolismo , Estudios Retrospectivos , Cognición/fisiología , Estudios Transversales , Anciano de 80 o más Años , Estudios Longitudinales , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estudios de Cohortes
16.
Acta Pharmacol Sin ; 45(5): 945-958, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38326624

RESUMEN

Glutamatergic neurons in ventral pallidum (VPGlu) were recently reported to mediate motivational and emotional behavior, but its role in opioid addiction still remains to be elucidated. In this study we investigated the function of VPGlu in the context-dependent heroin taking and seeking behavior in male rats under the ABA renewal paradigm. By use of cell-type-specific fiber photometry, we showed that the calcium activity of VPGlu were inhibited during heroin self-administration and context-induced relapse, but activated after extinction in a new context. The drug seeking behavior was accompanied by the decreased calcium signal of VPGlu. Chemogenetic manipulation of VPGlu bidirectionally regulated heroin taking and seeking behavior. Anterograde tracing showed that the lateral habenula, one of the epithalamic structures, was the major output region of VPGlu, and its neuronal activity was consistent with VPGlu in different phases of heroin addiction and contributed to the motivation for heroin. VPGlu axon terminals in LHb exhibited dynamic activity in different phases of heroin addiction. Activation of VPGlu-LHb circuit reduced heroin seeking behavior during context-induced relapse. Furthermore, the balance of excitation/inhibition from VP to LHb was shifted to enhanced glutamate transmission after extinction of heroin seeking motivation. Overall, the present study demonstrated that the activity of VPGlu was involved in the regulation of heroin addiction and identified the VPGlu-LHb pathway as a potential intervention to reduce heroin seeking motivation.


Asunto(s)
Prosencéfalo Basal , Ácido Glutámico , Dependencia de Heroína , Neuronas , Ratas Sprague-Dawley , Animales , Masculino , Dependencia de Heroína/metabolismo , Dependencia de Heroína/psicología , Prosencéfalo Basal/metabolismo , Ácido Glutámico/metabolismo , Neuronas/metabolismo , Comportamiento de Búsqueda de Drogas , Heroína , Ratas , Autoadministración , Habénula/metabolismo
17.
Brain ; 147(6): 1937-1952, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38279949

RESUMEN

In recent years there has been a renewed interest in the basal forebrain cholinergic system as a target for the treatment of cognitive impairments in patients with Parkinson's disease, due in part to the need to explore novel approaches to treat the cognitive symptoms of the disease and in part to the development of more refined imaging tools that have made it possible to monitor the progressive changes in the structure and function of the basal forebrain system as they evolve over time. In parallel, emerging technologies allowing the derivation of authentic basal forebrain cholinergic neurons from human pluripotent stem cells are providing new powerful tools for the exploration of cholinergic neuron replacement in animal models of Parkinson's disease-like cognitive decline. In this review, we discuss the rationale for cholinergic cell replacement as a potential therapeutic strategy in Parkinson's disease and how this approach can be explored in rodent models of Parkinson's disease-like cognitive decline, building on insights gained from the extensive animal experimental work that was performed in rodent and primate models in the 1980s and 90s. Although therapies targeting the cholinergic system have so far been focused mainly on patients with Alzheimer's disease, Parkinson's disease with dementia may be a more relevant condition. In Parkinson's disease with dementia, the basal forebrain system undergoes progressive degeneration and the magnitude of cholinergic cell loss has been shown to correlate with the level of cognitive impairment. Thus, cell therapy aimed to replace the lost basal forebrain cholinergic neurons represents an interesting strategy to combat some of the major cognitive impairments in patients with Parkinson's disease dementia.


Asunto(s)
Prosencéfalo Basal , Neuronas Colinérgicas , Enfermedad de Parkinson , Humanos , Prosencéfalo Basal/metabolismo , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/metabolismo , Animales , Neuronas Colinérgicas/metabolismo
18.
Brain Behav Immun ; 117: 347-355, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38266662

RESUMEN

Human Immunodeficiency Virus-1 (HIV) infection of the brain induces HIV-associated neurocognitive disorders (HAND). The set of molecular events employed by HIV to drive cognitive impairments in people living with HIV are diverse and remain not completely understood. We have shown that the HIV envelope protein gp120 promotes loss of synapses and decreases performance on cognitive tasks through the p75 neurotrophin receptor (p75NTR). This receptor is abundant on cholinergic neurons of the basal forebrain and contributes to cognitive impairment in various neurological disorders. In this study, we examined cholinergic neurons of gp120 transgenic (gp120tg) mice for signs of degeneration. We observed that the number of choline acetyltransferase-expressing cells is decreased in old (12-14-month-old) gp120tg mice when compared to age matched wild type. In the same animals, we observed an increase in the levels of pro-nerve growth factor, a ligand of p75NTR, as well as a disruption of consolidation of extinction of conditioned fear, a behavior regulated by cholinergic neurons of the basal forebrain. Both biochemical and behavioral outcomes of gp120tg mice were rescued by the deletion of the p75NTR gene, strongly supporting the role that this receptor plays in the neurotoxic effects of gp120. These data indicate that future p75NTR-directed pharmacotherapies could provide an adjunct therapy against synaptic simplification caused by HIV.


Asunto(s)
Prosencéfalo Basal , Infecciones por VIH , VIH-1 , Ratones , Animales , Humanos , Lactante , Receptor de Factor de Crecimiento Nervioso/metabolismo , Ratones Transgénicos , VIH-1/metabolismo , Prosencéfalo Basal/metabolismo , Neuronas Colinérgicas/metabolismo , Infecciones por VIH/metabolismo
19.
CNS Neurosci Ther ; 30(2): e14365, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-37485782

RESUMEN

AIMS: To verify the hypothesis that an enriched environment (EE) alleviates sleep deprivation-induced fear memory impairment by modulating the basal forebrain (BF) PIEZO1/calpain/autophagy pathway. METHODS: Eight-week-old male mice were housed in a closed, isolated environment (CE) or an EE, before 6-h total sleep deprivation. Changes in fear memory after sleep deprivation were observed using an inhibitory avoidance test. Alterations in BF PIEZO1/calpain/autophagy signaling were detected. The PIEZO1 agonist Yoda1 or inhibitor GsMTx4, the calpain inhibitor PD151746, and the autophagy inducer rapamycin or inhibitor 3-MA were injected into the bilateral BF to investigate the pathways involved in the memory-maintaining role of EE in sleep-deprived mice. RESULTS: Mice housed in EE performed better than CE mice in short- and long-term fear memory tests after sleep deprivation. Sleep deprivation resulted in increased PIEZO1 expression, full-length tropomyosin receptor kinase B (TrkB-FL) degradation, and autophagy, as reflected by increased LC3 II/I ratio, enhanced p62 degradation, increased TFEB expression and nuclear translocation, and decreased TFEB phosphorylation. These molecular changes were partially reversed by EE treatment. Microinjection of Yoda1 or rapamycin into the bilateral basal forebrain induced excessive autophagy and eliminated the cognition-protective effects of EE. Bilateral basal forebrain microinjection of GsMTx4, PD151746, or 3-MA mimicked the cognitive protective and autophagy inhibitory effects of EE in sleep-deprived mice. CONCLUSIONS: EE combats sleep deprivation-induced fear memory impairments by inhibiting the BF PIEZO1/calpain/autophagy pathway.


Asunto(s)
Acrilatos , Prosencéfalo Basal , Calpaína , Animales , Masculino , Ratones , Autofagia , Prosencéfalo Basal/metabolismo , Calpaína/metabolismo , Miedo , Trastornos de la Memoria/etiología , Trastornos de la Memoria/terapia , Transducción de Señal , Sirolimus/farmacología , Sirolimus/uso terapéutico , Privación de Sueño/complicaciones
20.
Ann Neurol ; 95(3): 442-458, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38062617

RESUMEN

OBJECTIVE: X-linked adrenoleukodystrophy is caused by mutations in the peroxisomal half-transporter ABCD1. The most common manifestation is adrenomyeloneuropathy, a hereditary spastic paraplegia of adulthood. The present study set out to understand the role of neuronal ABCD1 in mice and humans with adrenomyeloneuropathy. METHODS: Neuronal expression of ABCD1 during development was assessed in mice and humans. ABCD1-deficient mice and human brain tissues were examined for corresponding pathology. Next, we silenced ABCD1 in cholinergic Sh-sy5y neurons to investigate its impact on neuronal function. Finally, we tested adeno-associated virus vector-mediated ABCD1 delivery to the brain in mice with adrenomyeloneuropathy. RESULTS: ABCD1 is highly expressed in neurons located in the periaqueductal gray matter, basal forebrain and hypothalamus. In ABCD1-deficient mice (Abcd1-/y), these structures showed mild accumulations of α-synuclein. Similarly, healthy human controls had high expression of ABCD1 in deep gray nuclei, whereas X-ALD patients showed increased levels of phosphorylated tau, gliosis, and complement activation in those same regions, albeit not to the degree seen in neurodegenerative tauopathies. Silencing ABCD1 in Sh-sy5y neurons impaired expression of functional proteins and decreased acetylcholine levels, similar to observations in plasma of Abcd1-/y mice. Notably, hind limb clasping in Abcd1-/y mice was corrected through transduction of ABCD1 in basal forebrain neurons following intracerebroventricular gene delivery. INTERPRETATION: Our study suggests that the basal forebrain-cortical cholinergic pathway may contribute to dysfunction in adrenomyeloneuropathy. Rescuing peroxisomal transport activity in basal forebrain neurons and supporting glial cells might represent a viable therapeutic strategy. ANN NEUROL 2024;95:442-458.


Asunto(s)
Adrenoleucodistrofia , Prosencéfalo Basal , Neuroblastoma , Humanos , Animales , Ratones , Adulto , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Prosencéfalo Basal/metabolismo , Neuronas/metabolismo , Colinérgicos , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA