Basal Forebrain Cellular Mechanisms of Cortical Activation

皮质激活的基底前脑细胞机制

• 批准号: 8413399
• 负责人: Robert W McCarley
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413399
• 关键词: Acoustic Stimulation; Action Potentials; Affect; Alzheimer' s Disease; Anterior; Attention; Auditory; Auditory area; Basic Science; Binding; Biological Models; Brain; Brain Stem; Brain region; Carbachol; Cations; Cerebral cortex; Cholinergic Agonists; Coma; Data; Development; Disease; Electroencephalogram; Elements; Exhibits; Financial compensation; Fluorescence; Frequencies; Funding; Future; Genetic; Grant; Halorhodopsins; Immunohistochemistry; In Vitro; Injection of therapeutic agent; Ion Channel; Ions; Knock-in Mouse; Knock-out; Laboratories; Lesion; Light; Measures; Mediating; Memory; Methodology; Methods; Military Personnel; Molecular; Mus; Muscarinic M3 Receptor; Muscarinics; Neurons; Neurotransmitter Receptor; Neurotransmitters; Parvalbumins; Patients; Perception; Polysomnography; Population; Procedures; REM Sleep; RNA; Receptor Activation; Regulation; Research; Role; Schizophrenia; Sensory; Series; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Wake Cycle; Slice; Small Interfering RNA; Sodium; Symptoms; Synapses; System; Techniques; Testing; Toxin; Veterans; Viral Vector; Visual Cortex; Wakefulness; Work; alertness; basal forebrain; basal forebrain cholinergic neurons; base; cell assembly; cell type; cholinergic; cholinergic neuron; cingulate cortex; executive function; gamma-Aminobutyric Acid; hypocretin; improved; in vivo; information processing; neural circuit; novel; novel strategies; optogenetics; orexin B receptor; patch clamp; programs; receptor; recombinase; research study; response; sleep regulation; therapeutic target; tool; transcriptional coactivator p75; voltage clamp

DESCRIPTION (provided by applicant): How do the states of wakefulness and sleep enhance the processing of information? The answer to this question involves the ability of the brain to synchronize the activities of assemblies of neurons by means of neuronal oscillations so that salient pieces of information are bound together in coherent percepts and synaptic connections between related neurons are strengthened, as originally proposed by Donald Hebb. The frequency, regional distribution and amplitude of such neuronal oscillations vary across the sleep-wake cycle. In particular, gamma oscillations (30-80 Hz or broader, centered on 40 Hz) are a prominent feature of the electroencephalogram (EEG) during waking and REM sleep. These oscillations are thought to be essential for brain functions such as attention, perception, and memory formation. Work from our group and from others has demonstrated gamma abnormalities in prefrontal and primary sensory (auditory and visual) cortices in schizophrenic patients. Furthermore, gamma deficits are a prominent feature of sleep disorders, coma, and Alzheimer's disease, other conditions prevalent in veterans and military personnel. Modulation of gamma oscillations thus represents a promising therapeutic target to treat symptoms of these disorders. This proposal focuses on the modulation of cortical activation and gamma oscillations by the basal forebrain (BF) neuronal projections to the cerebral cortex, since, in a recent study, extensive lesions of the BF region revealed dramatic reductions in cortical activation/gamma activity leading to a coma-like state. While such lesions point to the importance of BF, they do not tell us which specific BF cell types are important for cortical activation, how BF is influenced by other brain regions and neurotransmitters, and which circuits and neurotransmitters would be optimal treatment targets. Building on the methodologies developed in the previous grant cycle and following our laboratory's strength and track record of using a multilevel approach, the proposed experiments use integrated molecular, in vitro, and in vivo (systems) methods in mice to provide optimal understanding of the neural circuits studied. In the first series of experiments novel 'optogenetic light- activated ion channels will be inserted into specific BF subpopulations (cholinergic and GABAergic neurons containing parvalbumin) to study the effect of activating or inhibiting these specific neuronal cell types on cortical activation/gamma activity. Polysomnographic recordings will determine the effect of these manipulations on sleep and wakefulness. Cortical local field potential (LFP) recordings will be used to gain a precise determination of local gamma oscillations in three different cortical regions affected by sleep deprivation and exhibiting abnormalities in schizophrenia. In addition, Fos immunohistochemistry will be used to provide a spatial and cell-type specific analysis of cortical activation following light stimulation of theseBF subpopulations. Following our successful use of small interfering RNA (siRNA) in the brainstem, the same technique will be used to knockdown orexin receptors in the BF and reveal their role in sleep-wake control, providing reversibility without the potential confound of developmental compensation often seen with constitutive knockouts. The selective toxin mu p75-saporin will be used to investigate the role of cholinergic BF neurons in the regulation of wakefulness, and the effect of orexins. In the last series of experiments we will use GAD67-GFP knock-in mice, a novel genetic tool validated in the previous grant cycle, to identify cortically projecting BF GABA neurons in vitro. Using patch-clamp recordings we will reveal their modulation by cholinergic and orexinergic compounds and determine the receptors and ion channels activated. In summary, we propose to use state-of-the-art methods to identify the cellular and molecular components of the BF projections to the cortex modulating wakefulness and cortical gamma activity. We thereby lay the groundwork for targeted therapies to improve alertness, attention, and executive function in conditions that affect the Veteran population such as schizophrenia, Alzheimer's disease and sleep disorders.

描述（由申请人提供）：