Cell type-specific long-range connections of basal forebrain circuit.
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ABSTRACT:
SUBMITTER: Do JP
PROVIDER: S-EPMC5095704 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The mammalian basal forebrain (BF) has important roles in controlling sleep and wakefulness, but the underlying neural circuit remains poorly understood. We examined the BF circuit by recording and optogenetically perturbing the activity of four genetically defined cell types across sleep-wake cycles and by comprehensively mapping their synaptic connections. Recordings from channelrhodopsin-2 (ChR2)-tagged neurons revealed that three BF cell types, cholinergic, glutamatergic and parvalbumin-positive (PV+) GABAergic neurons, were more active during wakefulness and rapid eye movement (REM) sleep (wake/REM active) than during non-REM (NREM) sleep, and activation of each cell type rapidly induced wakefulness. By contrast, activation of somatostatin-positive (SOM+) GABAergic neurons promoted NREM sleep, although only some of them were NREM active. Synaptically, the wake-promoting neurons were organized hierarchically by glutamatergic→cholinergic→PV+ neuron excitatory connections, and they all received inhibition from SOM+ neurons. Together, these findings reveal the basic organization of the BF circuit for sleep-wake control.
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Project description:Decisions about when to act are critical for survival in humans as in animals, but how a desire is translated into the decision that an action is worth taking at any particular point in time is incompletely understood. Here we show that a simple model developed to explain when animals decide it is worth taking an action also explains a significant portion of the variance in timing observed when humans take voluntary actions. The model focuses on the current environment's potential for reward, the timing of the individual's own recent actions, and the outcomes of those actions. We show, by using ultrahigh-field MRI scanning, that in addition to anterior cingulate cortex within medial frontal cortex, a group of subcortical structures including striatum, substantia nigra, basal forebrain (BF), pedunculopontine nucleus (PPN), and habenula (HB) encode trial-by-trial variation in action time. Further analysis of the activity patterns found in each area together with psychophysiological interaction analysis and structural equation modeling suggested a model in which BF integrates contextual information that will influence the decision about when to act and communicates this information, in parallel with PPN and HB influences, to nigrostriatal circuits. It is then in the nigrostriatal circuit that action initiation per se begins.
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Project description:Cortically projecting basal forebrain neurons play a critical role in learning and attention, and their degeneration accompanies age-related impairments in cognition. Despite the impressive anatomical and cell-type complexity of this system, currently available data suggest that basal forebrain neurons lack complexity in their response fields, with activity primarily reflecting only macro-level brain states such as sleep and wake, onset of relevant stimuli and/or reward obtainment. The current study examined the spiking activity of basal forebrain neuron populations across multiple phases of a selective attention task, addressing, in particular, the issue of complexity in ensemble firing patterns across time. Clustering techniques applied to the full population revealed a large number of distinct categories of task-phase-specific activity patterns. Unique population firing-rate vectors defined each task phase and most categories of task-phase-specific firing had counterparts with opposing firing patterns. An analogous set of task-phase-specific firing patterns was also observed in a population of posterior parietal cortex neurons. Thus, consistent with the known anatomical complexity, basal forebrain population dynamics are capable of differentially modulating their cortical targets according to the unique sets of environmental stimuli, motor requirements, and cognitive processes associated with different task phases.
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Project description:In songbirds, as in mammals, basal ganglia-forebrain circuits are necessary for the learning and production of complex motor behaviors; however, the precise role of these circuits remains unknown. It has recently been shown that a basal ganglia-forebrain circuit in the songbird, which projects directly to vocal-motor circuitry, has a premotor function driving exploration necessary for vocal learning. It has also been hypothesized that this circuit, known as the anterior forebrain pathway (AFP), may generate an instructive signal that improves performance in the motor pathway. Here, we show that the output of the AFP directly implements a motor correction that reduces vocal errors. We use disruptive auditory feedback, contingent on song pitch, to induce learned changes in song structure over the course of hours and find that reversible inactivation of the output of the AFP produces an immediate regression of these learned changes. Thus, the AFP is involved in generating an error-reducing bias, which could increase the efficiency of vocal exploration and instruct synaptic changes in the motor pathway. We also find that learned changes in the song generated by the AFP are incorporated into the motor pathway within 1 day. Our observations support a view that basal ganglia-related circuits directly implement behavioral adaptations that minimize errors and subsequently stabilize these adaptations by training premotor cortical areas.
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Project description:Genome-wide association studies in diverse populations have reproducibly associated variants within introns of FTO with increased risk for obesity and type-2 diabetes.While the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. Yet, no direct connection between the obesity-associated intronic variants and FTO expression or function has been made. We show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, primarily with the homeobox gene IRX3, rather than with FTO. 4C-seq samples for Fto/fto and Irx3/irx3a genes promoters in different samples: adult mouse brain, E9.5 mouse embryos and 24hpf zebrafish embryos.
2014-02-24 | E-GEOD-52830 | biostudies-arrayexpress
Project description:BackgroundThe degeneration of the cholinergic circuit from the basal forebrain to the hippocampus contributes to memory loss in patients suffering from Alzheimer's disease (AD). However, the internal relationships between the acetylcholine (Ach) cycle and memory decline during the early stages of AD currently remain unknown. Here, we investigate the mechanisms underlying the activation of the cholinergic circuit and its impact on learning and memory using APP/PS1 mice models.MethodsNovel object recognition and Morris water maze tests were used to measure learning and memory function. Magnetic resonance spectrum (MRS) imaging was applied to longitudinally track changes in neurochemical metabolism in APP/PS1 mice aged 2, 4, 6, and 8 months. The number of neurons and the deposition of Aβ plaques were measured using Nissl, immunohistochemistry, and Thioflavin S staining. We then employed a chemogenetic strategy to selectively activate the cholinergic circuit from the medial septal nucleus (MS) and the vertical limb of the diagonal band nucleus (VDB) on the basal forebrain to the hippocampus. MRS and immunoblotting techniques were used to measure the neurochemical metabolism levels and cholinergic-related proteins, respectively.ResultsWe found that the levels of choline (Cho) in the basal forebrain were markedly higher compared to other brain regions and that its decrease along with N-acetyl aspartate (NAA) levels in the hippocampus was accompanied by memory deficits in APP/PS1 mice aged 4, 6, and 8 months. In terms of pathology, we observed that the deposition of Aβ plaques gradually aggravated throughout the cerebral cortex and hippocampus in APP/PS1 mice aged 6 and 8 months, while no Aβ deposition was detected in the basal forebrain. In contrast, the activity of choline acetyltransferase (ChAT) enzyme in the basal forebrain was decreased at 6 months of age and the cholinergic neurons were lost in the basal forebrain at 8 months of age. In addition, the activation of the cholinergic circuit from the MS and VDB to the hippocampus using chemical genetics is able to improve learning and reduce memory impairment in APP/PS1 mice. Similarly, the levels of Cho in the basal forebrain; NAA in the hippocampus, as well as the expression of ChAT and vesicular acetylcholine transporter (vAchT) in the basal forebrain; and muscarinic acetylcholine receptor 2 (CHRM2) in the hippocampus all increased.ConclusionsThese findings demonstrate that the neurochemical Cho and NAA of the cholinergic circuit can be used as biomarkers to enable the early diagnosis of AD. In addition, memory impairment in APP/PS1 mice can be attenuated using chemical genetics-driven Ach cycle activity of the cholinergic circuit.
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Project description:Genome-wide association studies in diverse populations have reproducibly associated variants within introns of FTO with increased risk for obesity and type-2 diabetes.While the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. Yet, no direct connection between the obesity-associated intronic variants and FTO expression or function has been made. We show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, primarily with the homeobox gene IRX3, rather than with FTO.
2014-02-24 | GSE52830 | GEO