GSTDTAP  > 气候变化
DOI10.1126/science.abi4907
A spotlight on the elusive striatal cholinergic interneuron
Anna E. Ingebretson; Julia C. Lemos
2021-04-23
发表期刊Science
出版年2021
英文摘要The brain of the mouse, one of the most commonly used animal models in biomedical research, is composed of about 70 million neurons all working in concert to control behavioral outputs and promote survival. Yet, on page 361 of this issue, Helseth et al. ([ 1 ][1]) demonstrate that just one signaling pathway in striatal cholinergic interneurons, a cell type that makes up ∼1% of neurons in a brain region of ∼120,000 cells, has a profound regulatory role in shaping habitual learning and memory, a type of learning and memory that allows us to drive to work or get to the cereal aisle at the grocery store without even thinking about it. The dorsal striatum is a central brain region in a constellation of nuclei known as the basal ganglia. The basal ganglia plays an essential role in movement, action planning, reward learning, and goal-directed and habitual behaviors, as well as procedural learning ([ 2 ][2], [ 3 ][3]). Furthermore, several brain diseases are linked to basal ganglia dysfunction, including Parkinson's disease, Huntington's disease, depression, substance use disorders, Tourette's syndrome, and obsessive-compulsive disorder ([ 3 ][3], [ 4 ][4]). The majority of neurons in the dorsal striatum are inhibitory medium spiny projection neurons that are characterized by spiny protrusions where inputs from other neurons make contact ([ 5 ][5]). Medium spiny neurons have been a major focal point within the basal ganglia field because they make up ∼95% of the neurons in the striatum. By contrast, cholinergic interneurons comprise only 1 to 2% of all neurons in the region ([ 6 ][6]) and as such have historically been more elusive to study. Cholinergic interneurons are defined by their large non-spiny morphology, pacemaker-like action potential firing, and production of the neurotransmitter acetylcholine ([ 6 ][6]). Despite constituting only 1 to 2% of neurons in the striatum, their many axonal divisions and wide branching structures allow a single neuron to supply a large number of neighboring neurons with acetylcholine ([ 6 ][6]). Accordingly, cholinergic interneurons have powerful, wide-reaching effects that allow them to act as master regulators of striatal output. Cholinergic neurotransmission is necessary for normal striatal function; however, owing to the relative scarcity of this population, it has been difficult to identify the precise mechanisms through which cholinergic interneurons regulate other neuronal populations. New cutting-edge neuroscience tools have allowed researchers to identify and experimentally manipulate these cells. For example, recent studies determined that the pattern of cholinergic interneuron firing—not simply the overall rate—plays an important role in behavior and cognition. Striatal cholinergic interneurons display two different firing modes: a continuous, pacemaker-like firing pattern and an intermittent firing pattern in which a burst of action potentials is followed by a pause in firing ([ 7 ][7]). Behavioral studies showed that pauses in cholinergic firing occur at motivationally important moments. Pauses are critical for making associations between cues in the environment and specific outcomes in classical conditioning paradigms ([ 8 ][8]) and are also necessary for updating behavioral strategies in the face of changes in previously learned associations ([ 9 ][9]). Although several different cellular and circuit mechanisms can generate pauses in firing, one well-established mechanism is activation of inhibitory dopamine type 2 (D2) receptors located on cholinergic interneurons ([ 10 ][10], [ 11 ][11]). Dopaminergic and cholinergic systems are reciprocally connected within the striatum: Cholinergic transmission can both trigger and modulate dopamine release ([ 12 ][12], [ 13 ][13]), and dopamine released from terminals emanating from the midbrain into the dorsal striatum activates D2 receptors on cholinergic interneurons, which briefly inhibits firing ([ 11 ][11]). Helseth et al. demonstrate that cholinergic regulation of dopamine signaling in the dorsal striatum relies on the integrated stress response (ISR) pathway, a ubiquitous cell signaling pathway that is transiently engaged in response to different homeostatic challenges ([ 14 ][14]). Because the ISR pathway regulates protein synthesis and is therefore a major contributor to long-term synaptic plasticity, learning, and memory, it has emerged as a central focus of pharmacotherapeutic development. Phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α), a factor required for initiating protein translation, is required for activating the ISR pathway ([ 14 ][14]). To track how this pathway is engaged, Helseth et al. generated a new tool called selective phospho-eIF2α ORF (open reading frame) Tracking light (SPOTlight) that uses fluorophores to report when phosphorylated eIF2a expression is “on” or “off” ([ 1 ][1]). Using this tool, they made a surprising discovery: Despite its canonically transient expression, the ISR pathway was constitutively active in cholinergic interneurons. Dampening the firing activity of cholinergic interneurons reduced ISR pathway activation, indicating that the basal activity of these neurons promotes constitutive activation of the ISR pathway. Notably, disruption of the ISR pathway switched the function of D2 receptors on cholinergic interneurons from inhibitory to excitatory, fundamentally altering a key component of the “pause.” This same manipulation also disrupted D2 regulation of dopamine release. Consistent with the behavioral role of striatal cholinergic interneurons, disruption of the ISR pathway in cholinergic interneurons disrupted skill and habitual learning assayed by a Morris water maze and operant conditioning tasks, but left motor coordination intact. Intriguingly, the authors found that increased performance vigor, defined as the amount of energy and speed used in a task, influenced the behavioral results. Because dopamine signaling contributes to performance vigor, these findings suggest that blocking the ISR pathway in cholinergic interneurons affects local dopamine dynamics to shape striatal neuron output to brain regions supporting motor and cognitive functions. In addition to its substantial technical innovation, the study of Helseth et al. puts forth an entirely new and unrecognized role for the ISR pathway that not only is important for cholinergic interneuron activity but also supports D2 receptor–mediated inhibition of cholinergic interneurons. D2 receptor–mediated inhibition of cholinergic interneurons alters excitatory transmission at medium spiny neuron synapses, ultimately affecting the net output of the striatum ([ 15 ][15]). It is rare to find evidence that bas al activation of a signaling pathway, such as the ISR pathway, not only is critical to receptor function, but without it, the functional sign of the receptor is switched. Another surprising finding is that some of the behavioral consequences of ISR pathway disruption were only apparent in male mice. The findings of Helseth et al. reveal new topics for exploration in basal ganglia function. It is not yet clear what mechanisms drive constitutive activation of the ISR pathway in this sparse population of cells. Another question is how disruption of this pathway modifies D2 receptor function within striatal circuitry. Probing these mechanisms could reveal how firing patterns of cholinergic interneurons encode conditioned associations that support learning. In addition, the sexually divergent behavioral consequences of ISR pathway disruption in cholinergic interneurons highlight avenues for investigating key sex differences. These findings could have profound consequences for the therapeutic utility of treatments that target the ISR pathway. 1. [↵][16]1. A. R. Helseth et al ., Science 372, eabe1931 (2021). [OpenUrl][17][Abstract/FREE Full Text][18] 2. [↵][19]1. J. Cox, 2. I. B. Witten , Nat. Rev. Neurosci. 20, 482 (2019). [OpenUrl][20][CrossRef][21][PubMed][22] 3. [↵][23]1. D. M. Lipton, 2. B. J. Gonzales, 3. A. Citri , Front. Neurosci. 13, 1 (2019). 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领域气候变化 ; 资源环境
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专题气候变化
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Anna E. Ingebretson,Julia C. Lemos. A spotlight on the elusive striatal cholinergic interneuron[J]. Science,2021.
APA Anna E. Ingebretson,&Julia C. Lemos.(2021).A spotlight on the elusive striatal cholinergic interneuron.Science.
MLA Anna E. Ingebretson,et al."A spotlight on the elusive striatal cholinergic interneuron".Science (2021).
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