RESUMEN
Acetylcholine regulates various cognitive functions through broad cholinergic innervation. However, specific cholinergic subpopulations, circuits and molecular mechanisms underlying recognition memory remain largely unknown. Here we show that Ngfr+ cholinergic neurons in the substantia innominate (SI)/nucleus basalis of Meynert (nBM)-medial prefrontal cortex (mPFC) circuit selectively underlies recency judgements. Loss of nerve growth factor receptor (Ngfr-/- mice) reduced the excitability of cholinergic neurons in the SI/nBM-mPFC circuit but not in the medial septum (MS)-hippocampus pathway, and impaired temporal order memory but not novel object and object location recognition. Expression of Ngfr in Ngfr-/- SI/nBM restored defected temporal order memory. Fiber photometry revealed that acetylcholine release in mPFC not only predicted object encounters but also mediated recency judgments of objects, and such acetylcholine release was absent in Ngfr-/- mPFC. Chemogenetic and optogenetic inhibition of SI/nBM projection to mPFC in ChAT-Cre mice diminished mPFC acetylcholine release and deteriorated temporal order recognition. Impaired cholinergic activity led to a depolarizing shift of GABAergic inputs to mPFC pyramidal neurons, due to disturbed KCC2-mediated chloride gradients. Finally, potentiation of acetylcholine signaling upregulated KCC2 levels, restored GABAergic driving force and rescued temporal order recognition deficits in Ngfr-/- mice. Thus, NGFR-dependent SI/nBM-mPFC cholinergic circuit underlies temporal order recognition memory.
Asunto(s)
Acetilcolina , Neuronas Colinérgicas , Corteza Prefrontal , Animales , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiología , Neuronas Colinérgicas/metabolismo , Neuronas Colinérgicas/fisiología , Acetilcolina/metabolismo , Ratones , Masculino , Ratones Noqueados , Reconocimiento en Psicología/fisiología , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/fisiología , Ratones Endogámicos C57BL , Células Piramidales/metabolismo , Células Piramidales/fisiología , Hipocampo/metabolismo , Receptores de Factor de Crecimiento NerviosoRESUMEN
There is substantial evidence that neuromodulatory systems critically influence brain state dynamics; however, most work has been purely descriptive. Here, we quantify, using data combining local inactivation of the basal forebrain with simultaneous measurement of resting-state fMRI activity in the macaque, the causal role of long-range cholinergic input to the stabilization of brain states in the cerebral cortex. Local inactivation of the nucleus basalis of Meynert (nbM) leads to a decrease in the energy barriers required for an fMRI state transition in cortical ongoing activity. Moreover, the inactivation of particular nbM sub-regions predominantly affects information transfer in cortical regions known to receive direct anatomical projections. We demonstrate these results in a simple neurodynamical model of cholinergic impact on neuronal firing rates and slow hyperpolarizing adaptation currents. We conclude that the cholinergic system plays a critical role in stabilizing macroscale brain state dynamics.
Asunto(s)
Imagen por Resonancia Magnética , Animales , Núcleo Basal de Meynert/fisiología , Núcleo Basal de Meynert/metabolismo , Acetilcolina/metabolismo , Macaca mulatta , Masculino , Neuronas Colinérgicas/fisiología , Neuronas Colinérgicas/metabolismo , Corteza Cerebral/fisiología , Corteza Cerebral/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Modelos NeurológicosRESUMEN
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/metabolismoRESUMEN
The behavioral and neural effects of the endogenous release of acetylcholine following stimulation of the nucleus basalis (NB) of Meynert have been recently examined in two male monkeys (Qi et al., 2021). Counterintuitively, NB stimulation enhanced behavioral performance while broadening neural tuning in the prefrontal cortex (PFC). The mechanism by which a weaker mnemonic neural code could lead to better performance remains unclear. Here, we show that increased neural excitability in a simple continuous bump attractor model can induce broader neural tuning and decrease bump diffusion, provided neural rates are saturated. Increased memory precision in the model overrides memory accuracy, improving overall task performance. Moreover, we show that bump attractor dynamics can account for the nonuniform impact of neuromodulation on distractibility, depending on distractor distance from the target. Finally, we delve into the conditions under which bump attractor tuning and diffusion balance in biologically plausible heterogeneous network models. In these discrete bump attractor networks, we show that reducing spatial correlations or enhancing excitatory transmission can improve memory precision. Altogether, we provide a mechanistic understanding of how cholinergic neuromodulation controls spatial working memory through perturbed attractor dynamics in the PFC.
Asunto(s)
Memoria a Corto Plazo , Modelos Neurológicos , Corteza Prefrontal , Memoria Espacial , Corteza Prefrontal/fisiología , Memoria a Corto Plazo/fisiología , Memoria Espacial/fisiología , Animales , Acetilcolina/metabolismo , Masculino , Neuronas Colinérgicas/fisiología , Neuronas Colinérgicas/efectos de los fármacos , Núcleo Basal de Meynert/fisiologíaRESUMEN
Past studies have observed that brain atrophy may accelerate after surgical procedures. Furthermore, an association of systemic inflammation with neurodegeneration has been described. We hypothesize that postoperative interleukin (IL) levels in circulation as well as the perioperative change in interleukin levels are associated with increased postoperative atrophy in the Nucleus basalis magnocellularis (of Meynert, NBM) which is the major source of cortical acetylcholine. We analyzed data from the BioCog cohort which included patients ≥ 65 years presenting for elective major surgery (≥ 60min). Blood samples were taken before surgery and on the first postoperative day. Magnetic resonance imaging of the brain and neuropsychological assessments were conducted before surgery and after three months follow-up. We used linear regression analysis to determine the association of three interleukins (IL6, IL8 and IL18) with NBM atrophy (in % volume change from baseline before surgery to follow-up), as well as to examine the associations of NBM atrophy and volume with postoperative cognitive ability and perioperative cognitive change. Receiver-operating curves were used to determine the prognostic value of preoperative interleukin levels. For IL8 (N = 97) and IL18 (N = 217), but not IL6 (N = 240), we observed significant associations of higher postoperative IL levels at the first postoperative day with higher NBM atrophy at three months after surgery. Subsequent analyses suggested that in both IL8 and IL18, this association was driven by a more general association of chronically elevated IL levels and NBM atrophy, reflected by preoperative IL concentrations, rather than IL response to surgery, measured as the difference between pre- and postoperative IL concentrations. At follow-up, NBM volume was positively associated with the level of cognitive performance, but NBM atrophy was not significantly related to perioperative cognitive change. Prognostic value of preoperative IL concentrations for NBM atrophy was low. Our results suggest that an association of postoperative interleukin levels with NBM atrophy is driven by preoperatively elevated interleukins due to pre-existing inflammation, rather than perioperative change in interleukin levels in response to surgery and anesthesia. The BioCog study has been registered at clinicaltrials.gov on Oct 15, 2014 (NCT02265263).
Asunto(s)
Núcleo Basal de Meynert , Interleucina-18 , Humanos , Atrofia/patología , Núcleo Basal de Meynert/patología , Núcleo Basal de Meynert/fisiología , Inflamación/patología , Interleucina-8 , AncianoRESUMEN
BACKGROUND: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has shown potential for the treatment of mild-to-moderate Alzheimer's disease (AD). However, there is little evidence of whether NBM-DBS can improve cognitive functioning in patients with advanced AD. In addition, the mechanisms underlying the modulation of brain networks remain unclear. This study was aimed to assess the cognitive function and the resting-state connectivity following NBM-DBS in patients with advanced AD. METHODS: Eight patients with advanced AD underwent bilateral NBM-DBS and were followed up for 12 months. Clinical outcomes were assessed by neuropsychological examinations using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale. Resting-state functional magnetic resonance imaging and positron emission tomography data were also collected. RESULTS: The cognitive functioning of AD patients did not change from baseline to the 12-month follow-up. Interestingly, the MMSE score indicated clinical efficacy at 1 month of follow-up. At this time point, the connectivity between the hippocampal network and frontoparietal network tended to increase in the DBS-on state compared to the DBS-off state. Additionally, the increased functional connectivity between the parahippocampal gyrus (PHG) and the parietal cortex was associated with cognitive improvement. Further dynamic functional network analysis showed that NBM-DBS increased the proportion of the PHG-related connections, which was related to improved cognitive performance. CONCLUSION: The results indicated that NBM-DBS improves short-term cognitive performance in patients with advanced AD, which may be related to the modulation of multi-network connectivity patterns, and the hippocampus plays an important role within these networks. TRIAL REGISTRATION: ChiCTR, ChiCTR1900022324. Registered 5 April 2019-Prospective registration. https://www.chictr.org.cn/showproj.aspx?proj=37712.
Asunto(s)
Enfermedad de Alzheimer , Estimulación Encefálica Profunda , Humanos , Núcleo Basal de Meynert/diagnóstico por imagen , Núcleo Basal de Meynert/fisiología , Estimulación Encefálica Profunda/métodos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/terapia , Estudios Prospectivos , Tomografía Computarizada por Rayos X , Hipocampo/diagnóstico por imagenRESUMEN
The basal nucleus of Meynert (NBM) subserves critically important functions in attention, arousal and cognition via its profound modulation of neocortical activity and is emerging as a key target in Alzheimer's and Parkinson's dementias. Despite the crucial role of neocortical domains in pain perception, however, the NBM has not been studied in models of chronic pain. Here, using in vivo tetrode recordings in behaving mice, we report that beta and gamma oscillatory activity is evoked in the NBM by noxious stimuli and is facilitated at peak inflammatory pain-like behavior. Optogenetic and chemogenetic cell-specific, reversible manipulations of NBM cholinergic-GABAergic neurons reveal their role in endogenous control of nociceptive hypersensitivity, which are manifest via projections to the prelimbic cortex, resulting in layer 5-mediated antinociception. Our data unravel the importance of the NBM in top-down control of neocortical processing of pain-like behavior.
Asunto(s)
Prosencéfalo Basal , Dolor Crónico , Animales , Núcleo Basal de Meynert/fisiología , Colinérgicos , Neuronas Colinérgicas , RatonesRESUMEN
We present an experimental protocol to record neuronal activity during intermittent stimulation of nucleus basalis (NB), as macaque monkeys perform cognitive tasks. This protocol includes implantation of electrodes and generator devices to deliver electrical stimulation to NB using multiple approaches in monkeys. Direct stimulation of NB avoids peripheral cholinergic side effects, optimizes timing, and activates non-cholinergic projection neurons. We describe electrode preparation, surgery, and implantation for direct evaluation of how stimulation affects monkeys' behavior and neuronal activity. For complete details on the use and execution of this profile, please refer to Qi et al. (2021).
Asunto(s)
Núcleo Basal de Meynert , Macaca , Animales , Núcleo Basal de Meynert/fisiología , Estimulación Eléctrica , Haplorrinos , Neuronas/fisiologíaRESUMEN
The action of acetylcholine in the cortex is critical for cognitive functions and cholinergic drugs can improve functions such as attention and working memory. An alternative means of enhancing cholinergic neuromodulation in primates is the intermittent electrical stimulation of the cortical source of acetylcholine, the nucleus basalis (NB) of Meynert. NB stimulation generally increases firing rate of neurons in the prefrontal cortex, however its effects on single neurons are diverse and complex. We sought to understand how NB stimulation affects global measures of neural activity by recording and analyzing local field potentials (LFPs) in monkeys as they performed working memory tasks. NB stimulation primarily decreased power in the alpha frequency range during the delay interval of working memory tasks. The effect was consistent across variants of the task. No consistent modulation in the delay interval of the task was observed in the gamma frequency range, which has previously been implicated in the maintenance of working memory. Our results reveal global effects of cholinergic neuromodulation via deep brain stimulation, an emerging intervention for the improvement of cognitive function.
Asunto(s)
Núcleo Basal de Meynert , Memoria a Corto Plazo , Acetilcolina/farmacología , Animales , Núcleo Basal de Meynert/fisiología , Memoria a Corto Plazo/fisiología , Periodicidad , Corteza Prefrontal/fisiologíaRESUMEN
Acetylcholine plays a critical role in the neocortex. Cholinergic agonists and acetylcholinesterase inhibitors can enhance cognitive functioning, as does intermittent electrical stimulation of the cortical source of acetylcholine, the nucleus basalis (NB) of Meynert. Here we show in two male monkeys how NB stimulation affects working memory and alters its neural code. NB stimulation increases dorsolateral prefrontal activity during the delay period of spatial working memory tasks and broadens selectivity for stimuli but does not strengthen phasic responses to each neuron's optimal visual stimulus. Paradoxically, despite this decrease in neuronal selectivity, performance improves in many task conditions, likely indicating increased delay period stability. Performance under NB stimulation does decline if distractors similar to the target are presented, consistent with reduced prefrontal selectivity. Our results indicate that stimulation of the cholinergic forebrain increases prefrontal neural activity, and this neuromodulatory tone can improve cognitive performance, subject to a stability-accuracy tradeoff.
Asunto(s)
Núcleo Basal de Meynert/fisiología , Memoria a Corto Plazo/fisiología , Corteza Prefrontal/fisiología , Potenciales de Acción/fisiología , Animales , Conducta Animal , Estimulación Eléctrica , Macaca mulatta , Masculino , Neuronas/fisiología , Análisis y Desempeño de TareasRESUMEN
Memory and cognitive impairment as sequelae of neurodegeneration in Alzheimer's disease and age-related dementia are major health issues with increasing social and economic burden. Deep brain stimulation (DBS) has emerged as a potential treatment to slow or halt progression of the disease state. The selection of stimulation target is critical, and structures that have been targeted for memory and cognitive enhancement include the Papez circuit, structures projecting to the frontal lobe such as the ventral internal capsule, and the cholinergic forebrain. Recent human clinical and animal model results imply that DBS of the nucleus basalis of Meynert can induce a therapeutic modulation of neuronal activity. Benefits include enhanced activity across the cortical mantle, and potential for amelioration of neuropathological mechanisms associated with Alzheimer's disease. The choice of stimulation parameters is also critical. High-frequency, continuous stimulation is used for movement disorders as a way of inhibiting their output; however, no overexcitation has been hypothesized in Alzheimer's disease and lower stimulation frequency or intermittent patterns of stimulation (periods of stimulation interleaved with periods of no stimulation) are likely to be more effective for stimulation of the cholinergic forebrain. Efficacy and long-term tolerance in human patients remain open questions, though the cumulative experience gained by DBS for movement disorders provides assurance for the safety of the procedure.
Asunto(s)
Colinérgicos , Trastornos del Conocimiento/terapia , Estimulación Encefálica Profunda , Enfermedad de Alzheimer/patología , Animales , Núcleo Basal de Meynert/fisiología , Humanos , Prosencéfalo/fisiologíaRESUMEN
Retrieval deficit of long-term memory is a cardinal symptom of dementia and has been proposed to associate with abnormalities in the central cholinergic system. Difficulty in the retrieval of memory is experienced by healthy individuals and not limited to patients with neurological disorders that result in forgetfulness. The difficulty of retrieving memories is associated with various factors, such as how often the event was experienced or remembered, but it is unclear how the cholinergic system plays a role in the retrieval of memory formed by a daily routine (accumulated experience). To investigate this point, we trained rats moderately (for a week) or extensively (for a month) to detect a visual cue in a two-alternative forced-choice task. First, we confirmed the well-established memory in the extensively trained group was more resistant to the retrieval problem than recently acquired memory in the moderately trained group. Next, we tested the effect of a cholinesterase inhibitor, donepezil, on the retrieval of memory after a long no-task period in extensively trained rats. Pre-administration of donepezil improved performance and reduced the latency of task initiation compared to the saline-treated group. Finally, we lesioned cholinergic neurons of the nucleus basalis magnocellularis (NBM), which project to the entire neocortex, by injecting the cholinergic toxin 192 IgG-saporin. NBM-lesioned rats showed severely impaired task initiation and performance. These abilities recovered as the trials progressed, though they never reached the level observed in rats with intact NBM. These results suggest that acetylcholine released from the NBM contributes to the retrieval of well-established memory developed by a daily routine.
Asunto(s)
Acetilcolina/metabolismo , Núcleo Basal de Meynert/fisiología , Neuronas Colinérgicas/fisiología , Recuerdo Mental/fisiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Anticuerpos Monoclonales/farmacología , Núcleo Basal de Meynert/efectos de los fármacos , Núcleo Basal de Meynert/metabolismo , Colinérgicos/farmacología , Neuronas Colinérgicas/efectos de los fármacos , Neuronas Colinérgicas/metabolismo , Inhibidores de la Colinesterasa/farmacología , Donepezilo/farmacología , Recuerdo Mental/efectos de los fármacos , Neocórtex/efectos de los fármacos , Neocórtex/metabolismo , Neocórtex/fisiología , Ratas , Saporinas/farmacologíaRESUMEN
Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been clinically investigated in Alzheimer's disease (AD) and Lewy body dementia (LBD). However, the clinical effects are highly variable, which questions the suggested basic principles underlying these clinical trials. Therefore, preclinical and clinical data on the design of NBM stimulation experiments and its effects on behavioral and neurophysiological aspects are systematically reviewed here. Animal studies have shown that electrical stimulation of the NBM enhanced cognition, increased the release of acetylcholine, enhanced cerebral blood flow, released several neuroprotective factors, and facilitates plasticity of cortical and subcortical receptive fields. However, the translation of these outcomes to current clinical practice is hampered by the fact that mainly animals with an intact NBM were used, whereas most animals were stimulated unilaterally, with different stimulation paradigms for only restricted timeframes. Future animal research has to refine the NBM stimulation methods, using partially lesioned NBM nuclei, to better resemble the clinical situation in AD, and LBD. More preclinical data on the effect of stimulation of lesioned NBM should be present, before DBS of the NBM in human is explored further.
Asunto(s)
Núcleo Basal de Meynert/fisiología , Estimulación Encefálica Profunda , Acetilcolina/metabolismo , Animales , Núcleo Basal de Meynert/anatomía & histología , Biomarcadores , Circulación Cerebrovascular , Estudios Clínicos como Asunto , Conectoma , Estimulación Encefálica Profunda/métodos , Metabolismo Energético , Humanos , Modelos Animales , Plasticidad NeuronalRESUMEN
Understanding object-directed actions performed by others is central to everyday life. This ability is thought to rely on the interaction between the dorsal action observation network (AON) and a ventral object recognition pathway. On this view, the AON would encode action kinematics, and the ventral pathway, the most likely intention afforded by the objects. However, experimental evidence supporting this model is still scarce. Here, we aimed to disentangle the contribution of dorsal vs. ventral pathways to action comprehension by exploiting their differential tuning to low-spatial frequencies (LSFs) and high-spatial frequencies (HSFs). We filtered naturalistic action images to contain only LSF or HSF and measured behavioral performance and corticospinal excitability (CSE) using transcranial magnetic stimulation (TMS). Actions were embedded in congruent or incongruent scenarios as defined by the compatibility between grips and intentions afforded by the contextual objects. Behaviorally, participants were better at discriminating congruent actions in intact than LSF images. This effect was reversed for incongruent actions, with better performance for LSF than intact and HSF. These modulations were mirrored at the neurophysiological level, with greater CSE facilitation for congruent than incongruent actions for HSF and the opposite pattern for LSF images. Finally, only for LSF did we observe CSE modulations according to grip kinematics. While results point to differential dorsal (LSF) and ventral (HSF) contributions to action comprehension for grip and context encoding, respectively, the negative congruency effect for LSF images suggests that object processing may influence action perception not only through ventral-to-dorsal connections, but also through a dorsal-to-dorsal route involved in predictive processing.
Asunto(s)
Núcleo Basal de Meynert/fisiología , Comprensión/fisiología , Núcleo de Edinger-Westphal/fisiología , Percepción de Movimiento/fisiología , Actividad Motora/fisiología , Adolescente , Adulto , Mapeo Encefálico , Electromiografía , Femenino , Voluntarios Sanos , Humanos , Masculino , Vías Nerviosas/fisiología , Estimulación Luminosa , Análisis Espacial , Estimulación Magnética Transcraneal , Adulto JovenRESUMEN
In rodents, exploring through continuous whisking is a process resulted from sensorimotor networking among different layers of somatosensory cortex (SC) such as layer 5 (L5) or barrel field, and regions like the nucleus basalis of Meynert (NBM). NBM is densely packed with cholinergic fibers and its dysfunction leads to diminished acetylcholine release within SC, tactile deficits and Alzheimer's disease (AD)-like memory impairment. Using extracellular single-unit recording, we investigated mechanisms underlying changes in response characteristics of L5b neurons to single or paired deflection of selected principle and adjacent whiskers (PW and AW), following NBM electrical stimulation in normal rats or ibotenic acid-induced NBM lesion leading to potential tactile deficiency and memory loss during passive avoidance learning (PAL) in AD-like neuropathology. Our results indicated that NBM electrical stimulation decreased ON and OFF response magnitude in nearly half of the units upon vibrissal deflection. The larger the response was evoked to whisker deflection before NBM stimulation, the smaller it gets after stimulation. Neuronal spontaneous activity was not changed with NBM stimulation or lesion. Leading to more sublinear response summation and decreased condition-test ratio, NBM lesion decreased ON response magnitude and facilitation, increased AW surround inhibition in paired whisker deflection, increased excitatory and decreased inhibitory receptive fields, weakened information processing during whisking, and resulted in AD-like declined PAL performance. These findings provide further understandings to develop translational approaches in precision therapeutics to target highly specific regions such as NBM or SC, and pathways like cholinergic system involved in tactile and memory deficits in AD.
Asunto(s)
Núcleo Basal de Meynert/fisiología , Trastornos de la Memoria/fisiopatología , Corteza Somatosensorial/fisiología , Acetilcolina/metabolismo , Enfermedad de Alzheimer/patología , Animales , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/patología , Fibras Colinérgicas/metabolismo , Modelos Animales de Enfermedad , Estimulación Eléctrica , Masculino , Memoria/fisiología , Trastornos de la Memoria/metabolismo , Neuronas/metabolismo , Ratas , Ratas Wistar , Corteza Somatosensorial/metabolismo , Tacto/fisiología , Percepción del Tacto/fisiología , Vibrisas/fisiologíaRESUMEN
We examined the neural mechanisms for increases in regional cerebral blood flow (rCBF) in the neocortex associated with mastication, focusing on the cortical vasodilative system derived from the nucleus basalis of Meynert (NBM). In pentobarbital-anesthetized rats, parietal cortical rCBF was recorded simultaneously with electromyogram (EMG) of jaw muscles, local field potentials of frontal cortex, multi-unit activity of NBM neurons, and systemic mean arterial pressure (MAP). When spontaneous rhythmic EMG activity was observed with cortical desynchronization, an increase in NBM activity and a marked rCBF increase independent of MAP changes were observed. A similar rCBF increase was elicited by repetitive electrical stimulation of unilateral cortical masticatory areas. The magnitude of rCBF increase was partially attenuated by administration of the GABAergic agonist muscimol into the NBM. The rCBF increase persisted after immobilization with systemic muscle relaxant (vecuronium). rCBF did not change when jaw muscle activity was induced by electrical stimulation of the pyramidal tract. The results suggest that activation of NBM vasodilator neurons contributes at least in part to the rCBF increase associated with masticatory muscle activity, and that the NBM activation is induced by central commands from the motor cortex, independently of feedback from brainstem central pattern generator or contracting muscles.
Asunto(s)
Núcleo Basal de Meynert/irrigación sanguínea , Corteza Cerebral/irrigación sanguínea , Músculos Masticadores/fisiología , Vasodilatación/fisiología , Animales , Presión Arterial/fisiología , Núcleo Basal de Meynert/efectos de los fármacos , Núcleo Basal de Meynert/fisiología , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Estimulación Eléctrica/efectos adversos , Estimulación Eléctrica/métodos , Electromiografía/métodos , Lóbulo Frontal/fisiología , Agonistas de Receptores de GABA-A/administración & dosificación , Agonistas de Receptores de GABA-A/farmacología , Masculino , Músculos Masticadores/efectos de los fármacos , Muscimol/administración & dosificación , Muscimol/farmacología , Fármacos Neuromusculares no Despolarizantes/administración & dosificación , Fármacos Neuromusculares no Despolarizantes/farmacología , Neuronas/clasificación , Neuronas/efectos de los fármacos , Neuronas/fisiología , Ratas , Ratas Wistar , Bromuro de Vecuronio/administración & dosificación , Bromuro de Vecuronio/farmacologíaRESUMEN
The activity of neurons is determined by the balance between their excitatory and inhibitory synaptic inputs. Neurons in the avian nucleus magnocellularis (NM) integrate monosynaptic excitatory and polysynaptic inhibitory inputs from the auditory nerve, and transmit phase-locked output to higher auditory centers. The excitatory input is graded tonotopically, such that neurons tuned to higher frequency receive fewer, but larger, axon terminals. However, it remains unknown how the balance between excitatory and inhibitory inputs is determined in NM. We here examined synaptic and spike responses of NM neurons during stimulation of the auditory nerve in thick brain slices of chicken of both sexes, and found that the excitatory-inhibitory balance varied according to tonotopic region, ensuring reliable spike output across frequencies. Auditory nerve stimulation elicited IPSCs in NM neurons regardless of tonotopic region, but the dependence of IPSCs on intensity varied in a systematic way. In neurons tuned to low frequency, IPSCs appeared and increased in parallel with EPSCs with elevation of intensity, which expanded dynamic range by preventing saturation of spike generation. On the other hand, in neurons tuned to higher frequency, IPSCs were smaller than EPSCs and had higher thresholds for activation, thus facilitating high-fidelity transmission. Computer simulation confirmed that these differences in inhibitory input were optimally matched to the patterns of excitatory input, and enabled appropriate level of neuronal output for wide intensity and frequency ranges of sound in the auditory system.SIGNIFICANCE STATEMENT Neurons in nucleus magnocellularis encode timing information of sound across wide intensity ranges by integrating excitatory and inhibitory synaptic inputs from the auditory nerve, but underlying synaptic mechanisms of this integration are not fully understood. We here show that the excitatory-inhibitory relationship was expressed differentially at each tonotopic region; the relationship was linear in neurons tuned to low-frequency, expanding dynamic range by preventing saturation of spike generation; by contrast inhibitory input remained much smaller than excitatory input in neurons tuned to higher frequency, thus ensuring high-fidelity transmission. The tonotopic regulation of excitatory and inhibitory input optimized the output across frequencies and intensities, playing a fundamental role in the timing coding pathway in the auditory system.
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Núcleo Basal de Meynert/fisiología , Pollos/fisiología , Inhibición Neural/fisiología , Sinapsis/fisiología , Animales , Nervio Coclear/fisiología , Simulación por Computador , Estimulación Eléctrica , Fenómenos Electrofisiológicos/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Masculino , Percepción de la Altura Tonal/fisiología , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
The nucleus basalis of Meynert (nbM) was first described at the end of the 19th century and named after its discoverer, Theodor Meynert. The nbM contains a large population of cholinergic neurons that project their axons to the entire cortical mantle, the olfactory tubercle, and the amygdala. It has been functionally associated with the control of attention and maintenance of arousal, both key functions for appropriate learning and memory formation. This structure is well-conserved across vertebrates, although its degree of organization varies between species. Since early in the investigation of its functional and pathological significance, its degeneration has been linked to various major neuropsychiatric disorders. For instance, Lewy bodies, a hallmark in the diagnosis of Parkinson's disease, were originally described in the nbM. Since then, its involvement in other Lewy body and dementia-related disorders has been recognized. In the context of recent positive outcomes following nbM deep brain stimulation in subjects with dementia-associated disorders, we review the literature from an historical perspective focusing on how the nbM came into focus as a promising therapeutic option for patients with Alzheimer's disease. Moreover, we will discuss what is needed to further develop and widely implement this approach as well as examine novel medical indications for which nbM deep brain stimulation may prove beneficial.
Asunto(s)
Núcleo Basal de Meynert , Trastornos del Conocimiento/terapia , Estimulación Encefálica Profunda , Enfermedad de Alzheimer/historia , Enfermedad de Alzheimer/terapia , Núcleo Basal de Meynert/anatomía & histología , Núcleo Basal de Meynert/fisiología , Trastornos del Conocimiento/historia , Estimulación Encefálica Profunda/historia , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , HumanosRESUMEN
The cholinergic neurons in the nucleus basalis of Meynert (NBM) are among the first group of neurons known to become degenerated in Alzheimer's disease, and thus the NBM is proposed to be involved in learning and memory. The marginal division (MrD) of the striatum is a newly discovered subdivision at the ventromedial border of the mammalian striatum and is considered to be one part of the ventral striatum involved in learning and memory. The present study provided evidence to support the hypothesis that the MrD and the NBM were structurally connected at cellular and subcellular levels with functional implications in learning and memory. First, when wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) was stereotaxically injected into the NBM, fusiform neurons in the MrD were retrogradely labeled with WGA-HRP gray-blue particles and some of them were double stained in brown color by AchE staining method. Thus, cholinergic neurons of the MrD were shown to project to the neurons in the NBM. Second, in anterograde tract-tracing experiments where WGA-HRP was injected to the MrD, the labeled WGA-HRP was found to be anterogradely transported in axons from the MrD to the synaptic terminals with dendrites, axons, and perikaryons of the cholinergic neurons in the NBM when observed under an electronic microscope, indicating reciprocal structural connections between the MrD and the NBM. Third, when bilateral lesions of the MrD were injured with kainic acid in rats, degenerative terminals were observed in synapses of the NBM by an electronic microscope and severe learning and memory deficiency was found in these rats by the Y-maze behavioral test. Our results suggest reciprocal cholinergic connections between the MrD of the ventral striatum and the NBM, and implicate a role of the MrD-NBM pathway in learning and memory. The efferent fibers of cholinergic neurons in the NBM mainly project to the cortex, and severe reduction of the cholinergic innervation in the cortex is the common feature of Alzheimer's patients. The newly discovered cholinergic neural pathway between the MrD of the ventral striatum and the NBM is supposed involved in the memory circuitries of the brain and probably might play a role in the pathogenesis of the Alzheimer's disease.