Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity, and coordinates firing of groups of neurons. As a result, it changes the state ...of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here, we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss consequences of this signaling on behaviors related to drug abuse, attention, food intake, and affect. The diverse effects of acetylcholine depend on site of release, receptor subtypes, and target neuronal population; however, a common theme is that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action. The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors.
Acetylcholine changes the state of neuronal networks and modifies their response to internal and external inputs. Here, Picciotto et al. identify actions of cholinergic signaling on cellular and synaptic properties and discuss how it impacts behaviors related to drug abuse, attention, food intake, and affect.
Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood. Using mouse models, we show that ...interleukin-6 (IL-6) is the dominant cytokine inducible upon acute stress alone. Stress-inducible IL-6 is produced from brown adipocytes in a beta-3-adrenergic-receptor-dependent fashion. During stress, endocrine IL-6 is the required instructive signal for mediating hyperglycemia through hepatic gluconeogenesis, which is necessary for anticipating and fueling “fight or flight” responses. This adaptation comes at the cost of enhancing mortality to a subsequent inflammatory challenge. These findings provide a mechanistic understanding of the ontogeny and adaptive purpose of IL-6 as a bona fide stress hormone coordinating systemic immunometabolic reprogramming. This brain-brown fat-liver axis might provide new insights into brown adipose tissue as a stress-responsive endocrine organ and mechanistic insight into targeting this axis in the treatment of inflammatory and neuropsychiatric diseases.
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•IL-6 is the dominant endocrine cytokine induced by acute stress in mice•Stress-inducible IL-6 is produced in brown adipocytes via ADRB3 signaling•IL-6 is required for stress hyperglycemia and adaptive “fight or flight” responses•Stress-induced IL-6 decreases tolerance to a subsequent inflammatory challenge
During acute psychological stress, brown adipocytes initiate a chain of events mediated by adrenergic signaling and IL-6 release that metabolically fuels “fight or flight” adaptive responses but at the same time comes at an inflammatory cost.
There is a well-established connection between smoking and depression. Depressed individuals are over-represented among smokers, and ex-smokers often experience increased depressive symptoms ...immediately after stopping smoking. Nicotine in tobacco binds, activates and desensitizes nicotinic acetylcholine receptors (nAChRs), but it is not known whether activation or desensitization is more important for the effects of nicotine on depressive symptoms. Here we review, based on clinical and preclinical studies of nicotinic drugs, the hypothesis that blockade (rather than activation) of neuronal nAChRs might be important for the effects of nicotinic agents on depressive symptoms. The endogenous neurotransmitter for nAChRs is acetylcholine, and the effects of nicotine on depression-like behaviors support the idea that dysregulation of the cholinergic system might contribute to the etiology of major depressive disorder. Thus, pharmacological agents that limit acetylcholine signaling through neuronal nAChRs might be promising for the development of novel antidepressant medications.
Complex neural circuits in the mammalian brain develop through a combination of genetic instruction and activity-dependent refinement. The relative role of these factors and the form of neuronal ...activity responsible for circuit development is a matter of significant debate. In the mammalian visual system, retinal ganglion cell projections to the brain are mapped with respect to retinotopic location and eye of origin. We manipulated the pattern of spontaneous retinal waves present during development without changing overall activity levels through the transgenic expression of β2-nicotinic acetylcholine receptors in retinal ganglion cells of mice. We used this manipulation to demonstrate that spontaneous retinal activity is not just permissive, but instructive in the emergence of eye-specific segregation and retinotopic refinement in the mouse visual system. This suggests that specific patterns of spontaneous activity throughout the developing brain are essential in the emergence of specific and distinct patterns of neuronal connectivity.
► Before eye opening, spontaneous activity in the retina regulates brain development ► Not just the presence, but the pattern of activity shapes circuit development ► A correlation-based Hebb mechanism neatly captures this activity dependent process ► Tight gene regulation during development shapes activity and circuit formation
Symptoms of depression can be induced in humans through blockade of acetylcholinesterase (AChE) whereas antidepressant-like effects can be produced in animal models and some clinical trials by ...limiting activity of acetylcholine (ACh) receptors. Thus, ACh signaling could contribute to the etiology of mood regulation. To test this hypothesis, we administered the AChE inhibitor physostigmine to mice and demonstrated an increase in anxiety- and depression-like behaviors that was reversed by administration of nicotinic or muscarinic antagonists. The behavioral effects of physostigmine were also reversed by administration of the selective serotonin reuptake inhibitor fluoxetine. Administration of fluoxetine also increased AChE activity throughout the brain, with the greatest change in the hippocampus. To determine whether cholinergic signaling in the hippocampus could contribute to the systemic effects of cholinergic drugs, we infused physostigmine or virally delivered shRNAs targeting AChE into the hippocampus. Both pharmacological and molecular genetic decreases in hippocampal AChE activity increased anxiety- and depression-like behaviors and decreased resilience to repeated stress in a social defeat paradigm. The behavioral changes due to shRNA-mediated knockdown of AChE were rescued by coinfusion of an shRNA-resistant AChE transgene into the hippocampus and reversed by systemic administration of fluoxetine. These data demonstrate that ACh signaling in the hippocampus promotes behaviors related to anxiety and depression. The sensitivity of these effects to fluoxetine suggests that shRNA-mediated knockdown of hippocampal AChE represents a model for anxiety- and depression-like phenotypes. Furthermore, abnormalities in the cholinergic system may be critical for the etiology of mood disorders and could represent an endophenotype of depression.
The co-morbidity between smoking and mood disorders is striking. Preclinical and clinical studies of nicotinic effects on mood, anxiety, aggression, and related behaviors, such as irritability and ...agitation, suggest that smokers may use the nicotine in tobacco products as an attempt to self-medicate symptoms of affective disorders. The role of nicotinic acetylcholine receptors (nAChRs) in circuits regulating mood and anxiety is beginning to be elucidated in animal models, but the mechanisms underlying the effects of nicotine on aggression-related behavioral states (ARBS) are still not understood. Clinical trials of nicotine or nicotinic medications for neurological and psychiatric disorders have often found effects of nicotinic medications on ARBS, but few trials have studied these outcomes systematically. Similarly, the increase in ARBS resulting from smoking cessation can be resolved by nicotinic agents, but the effects of nicotinic medications on these types of mental states and behaviors in non-smokers are less well understood. Here we review the literature on the role of nAChRs in regulating mood and anxiety, and subsequently on the closely related construct of ARBS. We suggest avenues for future study to identify how nAChRs and nicotinic agents may play a role in these clinically important areas.
This article is part of the Special Issue entitled ‘The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition’.
•There is high co-morbidity between smoking and mood disorders.•Clinical trials have shown effects of nicotine on aggression-related behaviors.•Few trials of nicotine study aggression-related outcomes systematically.•Further studies nicotine and nAChR effects on aggression are necessary.
Optimal acetylcholine (ACh) signaling is important for sustained attention and facilitates learning and memory. At the same time, human and animal studies have demonstrated increased levels of ACh in ...the brain during depressive episodes and increased symptoms of anxiety, depression, and reactivity to stress when ACh breakdown is impaired. While it is possible that the neuromodulatory roles of ACh in cognitive and affective processes are distinct, one possibility is that homeostatic levels of ACh signaling are necessary for appropriate learning, but overly high levels of cholinergic signaling promote encoding of stressful events, leading to the negative encoding bias that is a core symptom of depression. In this review, we outline this hypothesis and suggest potential neural pathways and underlying mechanisms that may support a role for ACh signaling in negative encoding bias.
At baseline, adaptive Acetylcholine signaling allows for cognitive flexibility as well as appropriate behavioral responses to either rewarding stimuli or threats. Upon exposure to extreme or repeated threat or changes in the cholinergic system, increased acetycholine signaling can potentiate attention to stressful stimuli and may bias encoding toward negative experiences.
Rates of alcohol use disorder (AUD) have increased in women by 84% over the past ten years relative to a 35% increase in men. This substantive increase in female drinking is alarming given that women ...experience greater alcohol-related health consequences compared to men. Stress is strongly associated with all phases of alcohol addiction, including drinking initiation, maintenance, and relapse for both women and men, but plays an especially critical role for women. The purpose of the present narrative review is to highlight what is known about sex differences in the relationship between stress and drinking. The critical role stress reactivity and negative affect play in initiating and maintaining alcohol use in women is addressed, and the available evidence for sex differences in drinking for negative reinforcement as it relates to brain stress systems is presented. This review discusses the critical structures and neurotransmitters that may underlie sex differences in stress-related alcohol use (e.g., prefrontal cortex, amygdala, norepinephrine, corticotropin releasing factor, and dynorphin), the involvement of sex and stress in alcohol-induced neurodegeneration, and the role of ovarian hormones in stress-related drinking. Finally, the potential avenues for the development of sex-appropriate pharmacological and behavioral treatments for AUD are identified. Overall, women are generally more likely to drink to regulate negative affect and stress reactivity. Sex differences in the onset and maintenance of alcohol use begin to develop during adolescence, coinciding with exposure to early life stress. These factors continue to affect alcohol use into adulthood, when reduced responsivity to stress, increased affect-related psychiatric comorbidities and alcohol-induced neurodegeneration contribute to chronic and problematic alcohol use, particularly for women. However, current research is limited regarding the examination of sex in the initiation and maintenance of alcohol use. Probing brain stress systems and associated brain regions is an important future direction for developing sex-appropriate treatments to address the role of stress in AUD.
•Rates of AUD have increased in women by 84% in the past 10 years.•The consideration of sex in addiction research has historically been inadequate.•Stress plays a critical role in initiating and maintaining alcohol use in women.•Alterations in stress pathophysiology may drive continued alcohol use in women.•Treatments targeted at sex-dependent factors which maintain drinking is critical.
The neurotransmitter acetylcholine (ACh) plays a central role in the regulation of multiple cognitive and behavioral processes, including attention, learning, memory, motivation, anxiety, mood, ...appetite, and reward. As a result, understanding ACh dynamics in the brain is essential for elucidating the neural mechanisms underlying these processes. In vivo measurements of ACh in the brain have been challenging because of the low concentrations and rapid turnover of this neurotransmitter. Here, we review a number of techniques that have been developed to measure ACh levels in the brain in vivo. We follow this with a deeper focus on use of genetically encoded fluorescent sensors coupled with fiber photometry, an accessible technique that can be used to monitor neurotransmitter release with high temporal resolution and specificity. We conclude with a discussion of methods for analyzing fiber photometry data and their respective advantages and disadvantages. The development of genetically encoded fluorescent ACh sensors is revolutionizing the field of cholinergic signaling, allowing temporally precise measurement of ACh release in awake, behaving animals. Use of these sensors has already begun to contribute to a mechanistic understanding of cholinergic modulation of complex behaviors.
Protein phosphorylation is an essential step for the expression of long-term potentiation (LTP), a long-lasting, activity-dependent strengthening of synaptic transmission widely regarded as a ...cellular mechanism underlying learning and memory. At the core of LTP is the synaptic insertion of AMPA receptors (AMPARs) triggered by the NMDA receptor-dependent activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). However, the CaMKII substrate that increases AMPAR-mediated transmission during LTP remains elusive. Here, we identify the hippocampus-enriched TARPγ-8, but not TARPγ-2/3/4, as a critical CaMKII substrate for LTP. We found that LTP induction increases TARPγ-8 phosphorylation, and that CaMKII-dependent enhancement of AMPAR-mediated transmission requires CaMKII phosphorylation sites of TARPγ-8. Moreover, LTP and memory formation, but not basal transmission, are significantly impaired in mice lacking CaMKII phosphorylation sites of TARPγ-8. Together, these findings demonstrate that TARPγ-8 is a crucial mediator of CaMKII-dependent LTP and therefore a molecular target that controls synaptic plasticity and associated cognitive functions.
•CaMKIIα phosphorylates TARPγ-8 directly at S277 and S281•TARPγ-8 phosphorylation at CaMKIIα sites is enhanced during chemical LTP•CaMKIIα enhances AMPAR-mediated transmission via TARPγ-8 phosphorylation sites•CaMKIIα phosphorylation of TARPγ-8 is required for LTP and learning and memory
Park et al. report hippocampus-enriched TARPγ-8 as a critical CaMKIIα substrate for LTP and learning and memory. LTP increases TARPγ-8 phosphorylation, and this phosphorylation is required for CaMKII-dependent increase of AMPAR-mediated transmission, LTP, and fear conditioning.
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