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Chapter 36: Actions of acetylcholine in the cerebral cortex and thalamus and implications for function
Abstract
Publisher Summary The concerted investigation of cholinergic systems by a large number of scientists has yielded an unparalleled wealth of information from molecular sequencing of the nicotinic receptor-channel to the firing patterns of cholinergic neurons in behaving primates. Acetylcholine (ACh) can activate a wide variety of pre- and post-synaptic responses ranging from rapid excitation to prolonged inhibition on the ionic level to stimulation of phospholipid turnover or inhibition of adenylyl cyclase in the biochemical realm. This versatility of cholinergic neurons contributes to their involvement in a variety of normal and abnormal neuronal functions, such as those underlying learning and memory, arousal and attentiveness, sleep and Alzheimer's disease. Of the variety of cholinergic pathways present in the mammalian CNS, the ascending projections from the brainstem to the thalamus and from the basal forebrain to the cerebral cortex appear to be particularly important in the modulatory control of forebrain activity. The cholinergic receptors that have been implicated in this ascending modulation of forebrain activity are both of the muscarinic and nicotinic type, with prolonged changes in activity generally associated with muscarinic receptors and more phasic responses associated with nicotinic receptors. Pharmacologically, nicotinic receptors have traditionally been categorized into two main groups: neural (or ganglionic) and muscular. The nicotinic receptor-channel is a pentameric structure composed of, in order of mobility on SDS polyacrylamide gels, two α, one β, one γ (expressed in development; replaced by ɛ in adults) and one δ subunit surrounding a water-filled pore. Amino acid sequencing of subunits, which contain the binding site for receptor activation, revealed the presence of at least four distinct subtypes, termed α1x-4. These four different α subunits (αl, muscle; α2-4 neural) differ not only in their primary structure, but also in their pharmacological properties and their distribution in the CNS.
... These neurons project to all areas and layers of the cortex (Sarter and Bruno, 1997). The cholinergic projections modulate the response of pyramidal cells to other corticalglutamatergic inputs (McCormick, 1993), facilitating the bottom-up sensory information processing within the cortex (Figure 1; Muir et al., 1994;Sarter et al., 2001). Furthermore, the long radiating dendrites of the cholinergic BF neurons receive inputs from all the brainstem and hypothalamic arousal systems, for example cholinergic ponto-mesencephalic neurons, noradrenergic LC neurons, dopaminergic ventralmesencephalic neurons, histaminergic tubero-mammillary neurons and orexinergic perifornical neurons (Jones and Cuello, 1989;Panula et al., 1989;Zaborszky and Cullinan, 1996;Peyron et al., 1998;Semba et al., 1998). ...
... The cholinergic basal forebrain neurons have been implicated in mechanisms of synaptic plasticity, learning, memory, arousal and attention (McCormick, 1993;Leanza et al., 1996); all these functions are related to cortical activation (Jones, 2003). For instance, pharmacological manipulations of cholinergic receptors in extra-striate occipital and superior-medial parietal cortices affect attentional performance (Bentley et al., 2004), and lesions of the BF in monkeys also interfere with attention (Voytko et al., 1994). ...
... The cholinergic basal forebrain neurons are hyperpolarized by ACh released by brainstem or forebrain neurons; both muscarinic and nicotinic receptors are involved in this effect, and could modulate the cortical and forebrain activity during particular states across the sleep-waking cycle (McCormick, 1993;Khateb et al., 1997). In the cerebral cortex and in the hippocampus, Ach release is maximal during wakefulness and REM sleep (Jasper and Tessier, 1971;Marrosu et al., 1995), while it decreases during non-REM sleep (Arrigoni et al., 2010). ...
The basal forebrain (BF) cholinergic system has an important role in attentive functions. The cholinergic system can be activated by different inputs, and in particular, by orexin neurons, whose cell bodies are located within the postero-lateral hypothalamus. Recently the orexin-producing neurons have been proved to promote arousal and attention through their projections to the BF. The aim of this review article is to summarize the evidence showing that the orexin system contributes to attentional processing by an increase in cortical acetylcholine release and in cortical neurons activity.
... As mentioned at the beginning, the corticothalamic network are subject to the McCormick, 1993), which is associated with the disruption of sleep rhythms. ...
... The TRN neurons are inhibited by acetylcholine (Ach) released from projections of the brainstem PPT and LDT, as well as the basal forebrain. Ach hyperpolarizes TRN neurons and depolarizes TC relay neurons (McCormick andPrince, 1986, 1987;McCormick, 1993 hyperpolarizing potentials (Fuentealba et al., 2004), and these hyperpolarizing potentials could have a dendritic origin, similar to the T-current in TRN neurons. ...
... The TRN neurons are inhibited by acetylcholine (Ach) released from projections of the brainstem PPT and LDT, as well as the basal forebrain. Ach hyperpolarizes TRN neurons and depolarizes TC relay neurons (McCormick andPrince, 1986, 1987;McCormick, 1993 hyperpolarizing potentials (Fuentealba et al., 2004), and these hyperpolarizing potentials could have a dendritic origin, similar to the T-current in TRN neurons. ...
... Cholinergic neurons in the basal forebrain, which innervate all cortical regions (Mesulam, 1995), modulate neuronal excitability (Nicoll, 1988;McCormick and Williamson, 1989;McCormick, 1993) and inf luence learning and memory (Hagan and Morris, 1989;Fibiger, 1991;Winkler et al., 1995). Cholinergic neurons that innervate the cortex are silent during non-REM sleep but have tonic firing rates of ∼20 Hz during the awake state and and REM sleep (Mitchell et al., 1987). ...
... The effects of carbachol were simulated by reducing three potassium conductances, g K(Ca) , g K,M and g K,leak , underlying the I sAHP , I M and I K,leak respectively (Madison and Nicoll, 1984;McCormick, 1993). The primary effects of carbachol were simulated by a 75% reduction in g K(Ca) , a 12.5% reduction in g K,M and a 12.5% reduction in g K,leak . ...
... Neocortical neurons in a slice preparation of the rat visual cortex were stimulated with both conventional constant current pulses and f luctuating inputs that resembled the impact of synaptic inputs recorded in vivo. In previous studies using constant current pulses, acetylcholine significantly enhanced the firing rate by blocking the currents underlying spike frequency adaptation (Nicoll, 1988;McCormick and Williamson, 1989;McCormick, 1993). In contrast to the strong spike frequency adaptation evoked by a constant current pulse (Fig. 1a), injection of a f luctuating current into neocortical neurons reduced or completely eliminated pronounced spike frequency adaptation at room temperature (Fig. 1b). ...
Neocortical neurons in vivo are spontaneously active and intracellular recordings have revealed strongly fluctuating membrane potentials arising from the irregular arrival of excitatory and inhibitory synaptic potentials. In addition to these rapid fluctuations, more slowly changing influences from diffuse activation of neuromodulatory systems alter the excitability of cortical neurons by modulating a variety of potassium conductances. In particular, acetylcholine, which affects learning and memory, reduces the slow afterhyperpolarization, which contributes to spike frequency adaptation. We used whole cell patch clamp recordings of pyramidal neurons in neocortical slices and computational simulations to show, first, that when fluctuating inputs were added to a constant current pulse, spike frequency adaptation was reduced as the amplitude of the fluctuations was increased. High-frequency, high-amplitude fluctuating inputs that resembled in vivo conditions [1] elicited only weak spike frequency adaptation. Second, bath application of carbachol, a cholinergic agonist, significantly increased the firing rate in response to a fluctuating input but minimally displaced the spike times by less than 3 milliseconds, comparable to the spike jitter observed when a visual stimulus is repeated under in vivo conditions (see [2] for more details on experiments and simulations). These results suggest that cholinergic modulation may preserve information encoded in precise spike timing, but not in interspike intervals, and that cholinergic mechanisms other than those involving adaptation may contribute significantly to cholinergic modulation of learning and memory.
... Cholinergic neurons in the basal forebrain, which innervate all cortical regions [I], modulate neuronal excitability [2, 31 and influence learning and memory [4, 5, 61. Cholinergic reduction of spike freqiiency adaptation in cortical neurons in response to a square pulse input is considered an important mechanism for cholinergic control of neuronal excitability [2,3, 71, the generation of theta rhythms [8, 91, and cholinergic modulation of higher level functions [lo, 111. We used whole cell patch clamp recordings in neocortical slices and computational simulations to show that, in contrast to the strong spike frequency adaptation observed with square pulse inputs, spike frequency adaptation was reduced or absent with fluctuating inputs that resemble in vivo conditions [I,!?]. ...
... the firing rate by blocking the currents underlying spike frequency adaptation [2,3,71 (Fig. la and lc). Cholinergic reduction of adaption has also been linked to higher level processing through neural network models of learning and memory and theta wave generation [8,9,10,111. ...
... neuronal excitability [2,3], the reduction or lack of adaptation observed with the fluctuating inputs (which should be even less influential at 37OC [23] A cortical neuron is generally thought t o carry information in its average rate of spiking, but the timing of individual spikes may also be important [21,14,15,16,22] Since neurons function in a dynamic neuromodulatory environment, the code used by the nervous system must be stable during changes in neuromodulator concentrations. Modification of spike timing, implied by cholinergic reduction in spike frequency adaptation tp a square pulse input (Fig. 4 4 , might disrupt information conveyed by spike times. ...
Cholinergic neurons in the basal forebrain, which innervate all cortical regions (I), modulate neuronal excitability (2, 31 and influence learning and memory (4, 5, 61. Cholinergic reduc- tion of spike freqiiency adaptation in cortical neurons in response to a square pulse input is considered an important mechanism for cholinergic control of neuronal excitability (2, 3, 71, the generation of theta rhythms (8, 91, and cholinergic modulation of higher level functions (lo, 111. We used whole cell patch clamp recordings in neocortical slices and computational simulations to show that, in contrast to the strong spike frequency adaptation observed with square pulse inputs, spike frequency adaptation was reduced or absent with fluctuating inputs that resemble in vivo conditions (I,!?). Furthermore, unlike modulation of responses to square pulse inputs, displacement of spike times in response to fluctuating inputs following cholin- ergic modulation was less than three milliseconds, comparable to the spike jitter observed during visual stimulation under in vivo conditions (13). These results suggest that cholin- ergic modulation is compatible with a neural code based on precise spike timing (la, 15, 161 but not a spike interval code, and that cholinergic mechanisms other than those involving adaptation (17, 18, 191 may contribute significantly to cholinergic modulation of learning and memo y (2O). We stimulated neocortical neurons in the rat visual cortex with both conventional square pulse inputs and fluctuating inputs that resembled the impact of synaptic inputs recorded in vivo. In previous studies using square pulse inputs, xetylcholine significantly enhanced the firing rate by blocking the currents underlying spike frequency adaptation (2,3, 71 (Fig. la and lc). Cholinergic reduction of adaption has also been linked to higher level processing through neural network models of learning and memory and theta wave generation (8, 9, 10, 111. In contrast to the strong spike frequency adaptation evoked by a square pulse input (Fig. la), injection of a fluctuating current into neocortical neurons reduced or completely eliminated pronounced spike frequency adaptation (Fig. lb). Adaptation measured within a block of 20 trials was high only when square pulse inputs were used and became much weaker for fluctuating inputs (cf. 2a and 2b control; paired t test, k4.923, p < .001, N=10). Instead of a differential increase of excitability for the later period of stimulation due to a blockade of adaptation (Fig. 2a), cholinergic modulation increased the excitability more uniformly for the fluctuating input (Fig. 2b). Does cholinergic modulation of adaptation contribute to cholinergic control of excitabil- ity in a manner that depends on the form of input? The increase in excitability and the
... Here, we will review studies of cortical muscarinic neuromodulation of WM performance and recapitulate recent work from our laboratory and others exploring muscarinic neuropharmacology of persistent activity and WM representations in primate PFC. Whereas there are several excellent published synopses regarding the functions of cortical ACh (McCormick, 1993;Steriade, 2004;Picciotto et al., 2012;Venkatesan et al., 2020), nicotinic and muscarinic neuromodulation of cognition and WM (Sarter and Bruno, 1997;Robbins and Arnsten, 2009;Klinkenberg and Blokland, 2010;Wallace and Bertrand, 2013), we will primarily focus on neurophysiological and pharmacological studies in dorsolateral PFC of non-human primates in this review. ...
... In rodents, cortical M1 receptors are predominantly expressed postsynaptically (Levey, 1996) and are presumed to mediate the excitatory effect of muscarinic agonists on cortical activity in brain slices (McCormick, 1989(McCormick, , 1993McCormick et al., 1993). Autoradiography using M1R-and M2R-preferring compounds suggests that M1R laminar expression in monkey PFC is present in all layers with strong bands of expression in layers III and V, while M2Rs are enriched in layer III and V/VI in the PFC, with the exception of Walker's area 46, where the expression is predominantly in layer V (Lidow et al., 1989;Mrzljak et al., 1993). ...
Neuromodulation by acetylcholine plays a vital role in shaping the physiology and functions of cerebral cortex. Cholinergic neuromodulation influences brain-state transitions, controls the gating of cortical sensory stimulus responses, and has been shown to influence the generation and maintenance of persistent activity in prefrontal cortex. Here we review our current understanding of the role of muscarinic cholinergic receptors in primate prefrontal cortex during its engagement in the performance of working memory tasks. We summarize the localization of muscarinic receptors in prefrontal cortex, review the effects of muscarinic neuromodulation on arousal, working memory and cognitive control tasks, and describe the effects of muscarinic M1 receptor stimulation and blockade on the generation and maintenance of persistent activity of prefrontal neurons encoding working memory representations. Recent studies describing the pharmacological effects of M1 receptors on prefrontal persistent activity demonstrate the heterogeneity of muscarinic actions and delineate unexpected modulatory effects discovered in primate prefrontal cortex when compared with studies in rodents. Understanding the underlying mechanisms by which muscarinic receptors regulate prefrontal cognitive control circuitry will inform the search of muscarinic-based therapeutic targets in the treatment of neuropsychiatric disorders.
... Its name arises from the fact that this current is down-regulated by the presence of the neuromodulator acetylcholine through its action on the muscarinic receptor. At the simplest level, this current reduces firing activity since it is a potassium current [2,3]. However, this current has been implicated in many aspects of both individual cell and network activity. ...
... These conclusions, of course, assume that the only effect of acetylcholine is to downregulate the M-current. However, acetycholine has been observed to have other effects, including down-regulating an afterhyperpolarization current I AHP [3,37] and the leak current [1]. As indicated above, our work indicates that decreasing g L will increase the value of g * M . ...
In this work, we consider a general conductance-based neuron model with the inclusion of the acetycholine sensitive, M-current. We study bifurcations in the parameter space consisting of the applied current $I_{app}$ I a p p , the maximal conductance of the M-current $g_{M}$ g M and the conductance of the leak current $g_{L}$ g L . We give precise conditions for the model that ensure the existence of a Bogdanov–Takens (BT) point and show that such a point can occur by varying $I_{app}$ I a p p and $g_{M}$ g M . We discuss the case when the BT point becomes a Bogdanov–Takens–cusp (BTC) point and show that such a point can occur in the three-dimensional parameter space. The results of the bifurcation analysis are applied to different neuronal models and are verified and supplemented by numerical bifurcation diagrams generated using the package . We conclude that there is a transition in the neuronal excitability type organised by the BT point and the neuron switches from Class-I to Class-II as conductance of the M-current increases.
... Its name arises from the fact that this current is in down-regulated by the presence of the neuromodulator acetylcholine through its action on the muscarinic receptor. At the simplest level, this current reduces firing activity since it is a potassium current [2,3]. However, this current has been implicated in many aspects of both individual cell and network activity. ...
... These conclusions, of course, assume that the only affect of acetylcholine is to down-regulate the M-current. However, acetycholine has been observed to have other effects, including downregulating an afterhyperpolarization current I AHP [3,34] and the leak current [1]. Our work indicates that decreasing g L will increase the value of g * M , see eq. (24). ...
In this work, we consider a general conductance-based neuron model with the inclusion of the acetycholine sensitive, M-current. We study bifurcations in the parameter space consisting of the applied current, $I_{app}$ the maximal conductance of the M-current, $g_M$, and the conductance of the leak current, $g_L$. We give precise conditions for the model that ensure the existence of a Bogdanov-Takens (BT) point and show such a point can occur by varying $I_{app}$ and $g_{M}$. We discuss the case when the BT point becomes a Bogdanov-Takens-Cusp (BTC) point and show that such a point can occur in the three dimensional parameter space. The results of the bifurcation analysis are applied to different neuronal models and are verified and supplemented by numerical bifurcation diagrams generated using the package MATCONT. We conclude that there is a transition in the neuronal excitability type organized by the BT point and the neuron switches from Class-I to Class-II as conductance of the M-current increases.
... We also tested whether the type of awake state was a determining factor by comparing the change in coupling between two awake states-actively behaving versus quietly resting states-but found no significant difference (all p > 0.5, Wilcoxon rank-sum test, n = 3 mice; Figures S5E and S5F). Because depolarization alone was not responsible for the effects we observed on coupling (i.e., the up and down states were equivalent), we looked at the effect of various neuromodulators that have been shown to correlate with the brain state and affect neuronal properties (Constantinople and Bruno, 2011;Labarrera et al., 2018;McCormick, 1993;McGinley et al., 2015;Muñ oz et al., 2017;Polack et al., 2013). The neuromodulators acetylcholine (ACh) and noradrenaline (NA) activate not only pyramidal cells (McCormick, 1993;McCormick et al., 1991), in particular distal dendrites (Labarrera et al., 2018;Williams and Fletcher, 2019), but also surrounding dendrite-targeting inhibitory interneurons (Bergles et al., 1996;Muñ oz et al., 2017). ...
... Because depolarization alone was not responsible for the effects we observed on coupling (i.e., the up and down states were equivalent), we looked at the effect of various neuromodulators that have been shown to correlate with the brain state and affect neuronal properties (Constantinople and Bruno, 2011;Labarrera et al., 2018;McCormick, 1993;McGinley et al., 2015;Muñ oz et al., 2017;Polack et al., 2013). The neuromodulators acetylcholine (ACh) and noradrenaline (NA) activate not only pyramidal cells (McCormick, 1993;McCormick et al., 1991), in particular distal dendrites (Labarrera et al., 2018;Williams and Fletcher, 2019), but also surrounding dendrite-targeting inhibitory interneurons (Bergles et al., 1996;Muñ oz et al., 2017). The net effect of these neuromodulators on dendro-somatic coupling is therefore hard to predict. ...
The mystery of general anesthesia is that it specifically suppresses consciousness by disrupting feedback signaling in the brain, even when feedforward signaling and basic neuronal function are left relatively unchanged. The mechanism for such selectiveness is unknown. Here we show that three different anesthetics have the same disruptive influence on signaling along apical dendrites in cortical layer 5 pyramidal neurons in mice. We found that optogenetic depolarization of the distal apical dendrites caused robust spiking at the cell body under awake conditions that was blocked by anesthesia. Moreover, we found that blocking metabotropic glutamate and cholinergic receptors had the same effect on apical dendrite decoupling as anesthesia or inactivation of the higher-order thalamus. If feedback signaling occurs predominantly through apical dendrites, the cellular mechanism we found would explain not only how anesthesia selectively blocks this signaling but also why conscious perception depends on both cortico-cortical and thalamo-cortical connectivity.
... The primary source of cholinergic tone in the cortex is supplied by diffuse projects from a basal forebrain structure known as the nucleus basalis of Meynert (NBM). The NBM contains almost exclusively cholinergic neurons that project to all layers of the cortex and hippocampus and modulate the effects of glutamatergic afferents [27][28][29][30]. In AD, the NBM is one of the earliest structures to show signs of atrophy and neuronal loss [31,32]. ...
Introduction:
Alzheimer's disease (AD) requires novel therapeutic approaches due to limited efficacy of current treatments.
Areas covered:
This article explores AD as a manifestation of neurocircuit dysfunction and evaluates deep brain stimulation (DBS) as a potential intervention. Focusing on fornix-targeted stimulation (DBS-f), the article summarizes safety, feasibility, and outcomes observed in phase 1/2 trials, highlighting findings such as cognitive improvement, increased metabolism, and hippocampal growth. Topics for further study include optimization of electrode placement, and the role of stimulation-induced autobiographical-recall. Nucleus basalis of Meynert (DBS-NBM) DBS is also discussed and compared with DBS-f. Challenges with both DBS-f and DBS-NBM are identified, emphasizing the need for further research on optimal stimulation parameters. The article also reviews alternative DBS targets, including medial temporal lobe structures and the ventral capsule/ventral striatum.
Expert opinion:
Looking ahead, a phase-3 DBS-f trial, and the prospect of closed-loop stimulation using EEG-derived biomarkers or hippocampal theta activity are highlighted. Recent FDA-approved therapies and other neuromodulation techniques like temporal interference and low-intensity ultrasound are considered. The article concludes by underscoring the importance of imaging-based diagnosis and staging to allow for circuit-targeted therapies, given the heterogeneity of AD and varied stages of neurocircuit dysfunction.
... For example, the connection strengths in the inhibitory thalamothalamic feedback loop (G srs ) and the the full thalamothalamic circuit (z) exhibit correlations with the administration of various medication groups and neurochemicals, such as alpha blockers, selective serotonin reuptake inhibitors (SSRIs), diabetes medication, and alcohol. This could be attributed to the various efferent cholinergic [86,87] and serotoninergic [88] synapses that TRN receives, along with the complex calcium-dependent dynamics underlying its firing state and frequency [29], which would potentially be altered with the administration of these medications. The average thalamocortical circuit (y) exhibits significant correlations with biomarkers related to sleep quality and sleep debt, such as waking through sleep or daytime sleepiness. ...
Recent developments in mathematical modelling of EEG data enable estimation and tracking of otherwise-inaccessible neurophysiological parameters over the course of a night’s sleep. Likewise, advancements in wearable electronics have enabled easier & more affordable at-home collection of sleep EEG data. The convergence of these two advances, namely neurophysiological modelling for mobile sleep EEG, has the potential to significantly improve sleep assessments in research and the clinic. However, this subject area has received limited attention in existing literature. To address this, we used an established mathematical model of the corticothalamic system to analyze EEG power spectra from 5 datasets, spanning from in-lab, research-grade systems to at-home mobile EEG devices. In the present work, we compare the convergent and divergent features of the data and the estimated physiological model parameters. While data quality and characteristics differ considerably, several key patterns consistent with previous theoretical and empirical work are observed. During the transition from lighter to deeper NREM stages, i) the exponent of the aperiodic (1 /f ) spectral component is increased, ii) bottom-up thalamocortical drive is reduced, iii) corticocortical connection strengths are increased. This effect, which we observe in healthy individuals across all 5 datasets, is interestingly absent in individuals taking SSRI antidepressants, suggesting possible effects of ascending neuromodulatory systems on corticothalamic oscillations. Our results provide a proof-of-principle for the utility and feasibility of this physiological modelling-based approach to analyzing data from mobile EEG devices, providing a mechanistic measure of brain physiology during sleep at home or in the lab.
... In addition to these dopaminergic systems, there are several other neurotransmitter systems that have broad effects on cortical brain function, including degeneration of the cholinergic basal forebrain (Fyfe, 2018;Ray et al., 2018). These neurons project throughout the PFC and modulate glutamatergic pyramidal cells involved in attention, memory, and mood (McCormick, 1993). Degeneration of the forebrain appears to have significant implications for non-motor PD symptoms. ...
Parkinson’s disease (PD) is a prevalent neurodegenerative disorder characterized by both motor and non-motor symptoms, many of which are resistant to currently available treatments. Since the discovery that non-invasive transcranial magnetic stimulation (TMS) can cause dopamine release in PD patients, there has been growing interest in the use of TMS to fill existing gaps in the treatment continuum for PD. This review evaluates the safety and efficacy of a unique multifocal, bilateral Deep TMS protocol, which has been evaluated as a tool to address motor and non-motor symptoms of PD. Six published clinical trials have delivered a two-stage TMS protocol with an H-Coil targeting both the prefrontal cortex (PFC) and motor cortex (M1) bilaterally (220 PD patients in total; 108 from two randomized, sham-controlled studies; 112 from open label or registry studies). In all studies TMS was delivered to M1 bilaterally (Stage 1) and then to the PFC bilaterally (Stage 2) with approximately 900 pulses per stage. For Stage 1 (M1), two studies delivered 10 Hz at 90% motor threshold (MT) while four studies delivered 1 Hz at 110% MT. For Stage 2 (PFC), all studies delivered 10 Hz at 100% MT. The results suggest that this two-stage Deep TMS protocol is a safe, moderately effective treatment for motor symptoms of PD, and that severely impaired patients have the highest benefits. Deep TMS also improves mood symptoms and cognitive function in these patients. Further research is needed to establish optimal dosing and the long-term durability of treatment effects.
... The basal forebrain cholinergic system includes the nucleus basalis of Meynert (nucleus basalis magnocellularis in rodents), substantia innominata (NB/SI), the medial septal nucleus, and the horizontal and vertical limbs of the diagonal band of Broca. These regions modulate learning, memory, synaptic plasticity, arousal, and attention (McCormick, 1993;Leanza et al., 1996;Villano et al., 2017). The brainstem cholinergic system comprises the peduncolopontine nucleus and the laterodorsal pontine tegmental nucleus, which has been described as part of the ascending reticular activating system. ...
The hippocampus-prefrontal cortex (HPC-PFC) pathway plays a fundamental role in executive and emotional functions. Neurophysiological studies have begun to unveil the dynamics of HPC-PFC interaction in both immediate demands and long-term adaptations. Disruptions in HPC-PFC functional connectivity can contribute to neuropsychiatric symptoms observed in mental illnesses and neurological conditions, such as schizophrenia, depression, anxiety disorders, and Alzheimer’s disease. Given the role in functional and dysfunctional physiology, it is crucial to understand the mechanisms that modulate the dynamics of HPC-PFC communication. Two of the main mechanisms that regulate HPC-PFC interactions are synaptic plasticity and modulatory neurotransmission. Synaptic plasticity can be investigated inducing long-term potentiation or long-term depression, while spontaneous functional connectivity can be inferred by statistical dependencies between the local field potentials of both regions. In turn, several neurotransmitters, such as acetylcholine, dopamine, serotonin, noradrenaline, and endocannabinoids, can regulate the fine-tuning of HPC-PFC connectivity. Despite experimental evidence, the effects of neuromodulation on HPC-PFC neuronal dynamics from cellular to behavioral levels are not fully understood. The current literature lacks a review that focuses on the main neurotransmitter interactions with HPC-PFC activity. Here we reviewed studies showing the effects of the main neurotransmitter systems in long- and short-term HPC-PFC synaptic plasticity. We also looked for the neuromodulatory effects on HPC-PFC oscillatory coordination. Finally, we review the implications of HPC-PFC disruption in synaptic plasticity and functional connectivity on cognition and neuropsychiatric disorders. The comprehensive overview of these impairments could help better understand the role of neuromodulation in HPC-PFC communication and generate insights into the etiology and physiopathology of clinical conditions.
... In mouse TRN, optogenetic stimulation of cholinergic BF axons gives rise to fast, short latency nicotinic EPSCs and slow, sustained, muscarinic IPSCs (Sun et al. 2013;Pita-Almenar et al. 2014), whereas in the MGN of the guinea pig, iontophoretic application of ACh leads to an initial hyperpolarization followed by a long-lasting muscarinic-dependent depolarization. Thus, longterm effects of ACh attributable to muscarinic activation can directly depolarize thalamocortical projection neurons as well as attenuate TRN-mediated inhibition, leading to increased excitability and perhaps a transition to tonic firing (McCormick and Prince 1987;McCormick 1993). However, nicotinic receptors are prominently expressed on terminals of thalamocortical and corticothalamic afferent fibers (Lavine et al. 1997;Kawai et al. 2007;Sottile et al. 2017). ...
Many studies have implicated the basal forebrain (BF) as a potent regulator of sensory encoding even at the earliest stages of or cortical processing. The source of this regulation involves the well-documented corticopetal cholinergic projections from BF to primary cortical areas. However, the BF also projects to subcortical structures, including the thalamic reticular nucleus (TRN), which has abundant reciprocal connections with sensory thalamus. Here we present naturalistic auditory stimuli to the anesthetized rat while making simultaneous single-unit recordings from the ventral medial geniculate nucleus (MGN) and primary auditory cortex (A1) during electrical stimulation of the BF. Like primary visual cortex, we find that BF stimulation increases the trial-to-trial reliability of A1 neurons, and we relate these results to change in the response properties of MGN neurons. We discuss several lines of evidence that implicate the BF to thalamus pathway in the manifestation of BF-induced changes to cortical sensory processing and support our conclusions with supplementary TRN recordings, as well as studies in awake animals showing a strong relationship between endogenous BF activity and A1 reliability. Our findings suggest that the BF subcortical projections that modulate MGN play an important role in auditory processing.
... The indirect mechanism is a reduction of cholinergic tone by A 1 Rmediated inhibition of cholinergic arousal neurons (Rainnie et al., 1994;Porkka-Heiskanen et al., 1997). Acetylcholine inhibits slow oscillation in thalamocortical neurons (Curro Dossi et al., 1991;Steriade et al., 1991;McCormick, 1993); thus reduction of cholinergic tone is permissive for the expression of SWA. ...
Roughly one-third of the human lifetime is spent in sleep, yet the reason for sleep remains unclear. Understanding the physiologic function of sleep is crucial toward establishing optimal health. Several proposed concepts address different aspects of sleep physiology, including humoral and circuit-based theories of sleep-wake regulation, the homeostatic two-process model of sleep regulation, the theory of sleep as a state of adaptive inactivity, and observations that arousal state and sleep homeostasis can be dissociated in pathologic disorders. Currently, there is no model that places the regulation of arousal and sleep homeostasis in a unified conceptual framework. Adenosine is well known as a somnogenic substance that affects normal sleep-wake patterns through several mechanisms in various brain locations via A1 or A2A receptors (A1Rs or A2ARs). Many cells and processes appear to play a role in modulating the extracellular concentration of adenosine at neuronal A1R or A2AR sites. Emerging evidence suggests that A1Rs and A2ARs have different roles in the regulation of sleep. In this review, we propose a model in which A2ARs allow the brain to sleep, i.e., these receptors provide sleep gating, whereas A1Rs modulate the function of sleep, i.e., these receptors are essential for the expression and resolution of sleep need. In this model, sleep is considered a brain state established in the absence of arousing inputs.
... The fourth group (Ch4) of basal forebrain cholinergic neurons includes a loosely clustered arrangement of cholinergic neurons located in the nucleus basalis magnocellularis (nBM) and rostrally contiguous ventral pallidum/substantia innominata (Mesulam et al., 1983a,b). These neurons project diffusely to all layers and areas of the neocortical mantle (Bigl et al., 1982;Struble et al., 1986), in which the primary physiological effect of ACh is to modulate the response of pyramidal cells to other, particularly glutamatergic, cortical input (McCormick, 1993;Metherate and Ashe, 1993). This innervation of the neocortex by basal forebrain cholinergic neurons is an important mediator of cortical activation in support of cognitive function. ...
Cholinergic activation regulates cognitive function, particularly long-term memory consolidation. This Review presents an overview of the anatomical, neurochemical, and pharmacological evidence supporting the cholinergic regulation of Pavlovian contextual and cue-conditioned fear learning and extinction. Basal forebrain cholinergic neurons provide inputs to neocortical regions and subcortical limbic structures such as the hippocampus and amygdala. Pharmacological manipulations of muscarinic and nicotinic receptors support the role of cholinergic processes in the amygdala, hippocampus, and prefrontal cortex in modulating the learning and extinction of contexts or cues associated with threat. Additional evidence from lesion studies and analysis of in vivo acetylcholine release with microdialysis similarly support a critical role of cholinergic neurotransmission in corticoamygdalar or corticohippocampal circuits during acquisition of fear extinction. Although a few studies have suggested a complex role of cholinergic neurotransmission in the cellular plasticity essential for extinction learning, more work is required to elucidate the exact cholinergic mechanisms and physiological role of muscarinic and nicotinic receptors in these fear circuits. Such studies are important for elucidating the role of cholinergic neurotransmission in disorders such as posttraumatic stress disorder that involve deficits in extinction learning as well as for developing novel therapeutic approaches for such disorders.
... Although the rate-history approach can certainly be made more sophisticated, there are biological systems in which the technique in its simplest, current form likely would provide insights. In particular it would very exciting to apply it to spike trains produced by the neurons (Ahmed et al. 1998;Connors et al. 1982) that inspired Liu and Wang's model (2001) and/or to studies of modulation of I AHP (Abdul-Ghani et al. 1996;Madison et al. 1987;McCormick 1993). ...
For a slowly-varying stimulus, the simplest relationship between a neuron's input and output is a rate code, in which the spike rate is a unique function of the stimulus at that instant. In the case of spike-rate adaptation, there is no unique relationship between input and output, because the spike rate at any time depends both on the instantaneous stimulus and on prior spiking (the "history"). To improve the decoding of spike trains produced by neurons that show spike-rate adaptation, we developed a simple scheme that incorporates "history" into a rate code. We utilized this rate-history code successfully to decode spike trains produced by (1) mathematical models of a neuron in which the mechanism for adaptation (IAHP) is specified, and (2) the gastropyloric receptor (GPR2), a stretch-sensitive neuron in the stomatogastric nervous system of the crab Cancer borealis, that exhibits long-lasting adaptation of unknown origin. Moreover, when we modified the spike rate either mathematically in a model system or by applying neuromodulatory agents to the experimental system, we found that changes in the rate-history code could be related to the biophysical mechanisms responsible for altering the spiking.
... In other studies NE induces a reduction in principal (pyramidal) cells K þ currents, similar to the effects of a number of light-molecular weight neurotransmitters including acetylcholine (Krnjević et al., 1971;Krnjevic, 1993), dopamine (Pedarzani and Storm, 1995), serotonin (Segal, 1999) and histamine (Martín et al., 2001), as found in seminal studies in the hippocampus and later confirmed to be also present across different cortical areas. Among the K þ currents inhibited by NE are the I A and the slow after hyper-polarization current (sAHP) (Madison and Nicoll, 1982;Foehring et al., 1989;McCormick et al., 1991McCormick et al., , 1993McCormick, 1993). A prominent consequence of the elevation of NE levels is thus an increase in spontaneous firing frequency accompanied by a decrease in adaptation (defined as the progressive decrease of neuronal firing frequency following a square current injection) either by direct membrane depolarization or by reducing repolarizing currents. ...
... Cholinergic LDT/PPT neurons project to the thalamus, causing depolarization of relay and non-specific cortically projecting neurons via M 1 -type receptors but hyperpolarization of GABAergic thalamic reticular neurons via M 2 -type receptors (McCormick, 1993;Steriade et al., 1993). Both of these actions lead to the abolition of spindles and other EEG phenomena characteristic of deep slow-wave sleep. ...
Introduction The functional states of the central nervous system are determined not only by the inputs received from the external world but also by internally generated electrical and chemical signals. These internally generated signals are responsible for the generation of the states we call sleep and wakefulness and for the transition between states. Neurons generate electrical signals as a result of the uneven distribution of ions across their cell membranes and the passage of ions through pores (ion channels) in these membranes. Neurotransmitters (chemical signaling molecules) are released from the processes of neurons and affect the electrical signaling of target neurons (or muscles) by opening ion channels themselves or by modulating ion channels via second messenger systems. The electrical properties of neurons involved in the control of rapid eye movement (REM) sleep and wakefulness will be described separately. Here we focus on the localization and neurochemistry of neurotransmitters involved in the control of these states. A variety of different methodologies has been employed to investigate the neurotransmitter systems involved in control of behavioral states. Biochemical experiments have elucidated the pathways and enzymes involved in the synthesis, degradation, release and reuptake of different neurotransmitters. Immunohistochemical techniques have allowed the visualization of their cellular and subcellular distribution throughout the nervous system as well as the distribution of their receptors and uptake systems.
... See also Vu et al., 2015). In the cortical and thalamic relay neurons, notably, the H1-receptor and muscarinic receptor share common membrane channels and mechanisms to produce similar postsynaptic activation and to promote arousal (Reviewed in McCormick, 1992, 1993Haas et al., 2008). Nevertheless, if such compensation appears operational under the baseline conditions, it can be vulnerable during crucial situations and as such, deficient phenotypes may appear when facing behavioral challenges as shown by our results. ...
... One of them could be the promotion of the transition between the sleep and wake states. In fact, the extent of the cholinergic influence in auditory cortical processing depends on the alertness of the animal: during slow-wave sleep, the virtual absence of acetylcholine from the cortex would minimize single cell excitability by allowing a maximal K ϩ neuronal conductance (Krnjevic 1993) and maximizing the effectiveness of GABAergic inhibitory currents associated with the thalamic spindles (Lee and McCormick 1997;McCormick 1993;McCormick and Prince 1986). Tonic activation of the corticopetal cholinergic NB produced during the sleep-towake transition would produce a basal cholinergic tone activating high-affinity M 2 Rs on GABAergic interneurons, inhibiting wave-like release of GABA associated with the sleep state, and increasing the overall responsiveness of the auditory cortex to sensory stimuli. ...
3 other HighWire hosted articles: This article has been cited by [PDF] [Full Text] [Abstract] , August 1, 2009; 102 (2): 659-669. Modulation of GABAergic Transmission by Muscarinic Receptors in the Entorhinal [PDF] [Full Text] [Abstract] , Mechanism Underlying a Cortical Gate Using Large-Scale Modeling Breakdown of Effective Connectivity During Slow Wave Sleep: Investigating the [PDF] [Full Text] [Abstract] ,
... The observed decrease in the adaptation to the standard tones also agrees with diminished spike-frequency adaptation caused by ACh in other sensory areas (Metherate et al., 1992;McCormick, 1993;Martin-Cortecero and Nunez, 2014). Likewise, ACh affected SSA mainly through the activation of the muscarinic rather than the nicotinic receptors (Fig. 4G,H ). ...
Unlabelled:
Neural encoding of an ever-changing acoustic environment is a complex and demanding process that depends on modulation by neuroactive substances. Some neurons of the inferior colliculus (IC) exhibit "stimulus-specific adaptation" (SSA), i.e., a decrease in their response to a repetitive sound, but not to a rare one. Previous studies have demonstrated that acetylcholine (ACh) alters the frequency response areas of auditory neurons and therefore is important in the encoding of spectral information. Here, we address how microiontophoretic application of ACh modulates SSA in the IC of the anesthetized rat. We found that ACh decreased SSA in IC neurons by increasing the response to the repetitive tone. This effect was mainly mediated by muscarinic receptors. The strength of the cholinergic modulation depended on the baseline SSA level, exerting its greatest effect on neurons with intermediate SSA responses across IC subdivisions. Our data demonstrate that the increased availability of ACh exerts transient functional changes in partially adapting IC neurons, enhancing the sensory encoding of the ongoing stimulation. This effect potentially contributes to the propagation of ascending sensory-evoked afferent activity through the thalamus en route to the cortex.
Significance statement:
Neural encoding of an ever-changing acoustic environment is a complex and demanding task that may depend on the available levels of neuroactive substances. We explored how the cholinergic inputs affect the responses of neurons in the auditory midbrain that exhibit different degrees of stimulus-specific adaptation (SSA), i.e., a specific decrease in their response to a repeated sound that does not generalize to other, rare sounds. This work addresses the role of cholinergic synaptic inputs as well as the contribution of the muscarinic and nicotinic receptors on SSA. This is the first report on the role of neuromodulation on SSA, and the results contribute to our understanding of the cellular bases for processing low- and high-probability sounds.
... Consequently, and if synchrony represents a strong attractor as prior studies suggest [39,49], escaping it might depend on finely tuned combinations of multiple factors, such as neuronal membrane potential, excitability, probability of neurotransmitter release and synaptic depression. All these (and others) have been previously shown to be affected by (cholinergic) neuromodulation in complex and intricate manners [26,40,55,57,62,65,83,[91][92][93][94][95] which differ from one cell type to another [96]. Consequently, the (homeostatic) recovery [25,38] of one or more of these finely tuned factors, in one or more neuronal types, might move the system back into a parameter space within which synchrony naturally emerges [49]. ...
Background
Prolonged neuromodulatory regimes, such as those critically involved in promoting arousal and suppressing sleep-associated synchronous activity patterns, might be expected to trigger adaptation processes and, consequently, a decline in neuromodulator-driven effects. This possibility, however, has rarely been addressed.
Results
Using networks of cultured cortical neurons, acetylcholine microinjections and a novel closed-loop `synchrony-clamp¿ system, we found that acetylcholine pulses strongly suppressed network synchrony. Over the course of many hours, however, synchrony invariably reemerged, even when feedback was used to compensate for declining cholinergic efficacy. Network synchrony also reemerged following its initial suppression by noradrenaline, but this did not occlude the suppression of synchrony or its gradual reemergence following subsequent cholinergic input. Importantly, cholinergic efficacy could be restored and preserved over extended time scales by periodically withdrawing cholinergic input.
Conclusions
These findings indicate that the capacity of neuromodulators to suppress network synchrony is constrained by slow-acting, reactive processes. A multiplicity of neuromodulators and ultimately neuromodulator withdrawal periods might thus be necessary to cope with an inevitable reemergence of network synchrony.
... The central action of ACh is a depolarizing shift of the membrane potential of thalamocortical relay (TC) neurons, leading to cessation of rhythmic bursts and occurrence of tonic activity (McCormick, 1992a). One crucial step of the membrane depolarization in TC neuron is the inhibition of membrane K + currents that contribute to the standing outward current (I SO ) via G αq protein-coupled muscarinic ACh receptor (MAChR) stimulation (McCormick, 1993;Meuth et al., 2003;Broicher et al., 2008;Coulon et al., 2010;Bista et al., 2012). ...
Key points
During the behavioural states of sleep and wakefulness thalamocortical relay neurons fire action potentials in high frequency bursts or tonic sequences, respectively.
The modulation of specific K ⁺ channel types, termed TASK and TREK, allows these neurons to switch between the two modes of activity.
In this study we show that the signalling lipids phosphatidylinositol 4,5‐bisphosphate (PIP 2 ) and diacylglycerol (DAG), which are components of their membrane environment, switch on and shut off TREK and TASK channels, respectively.
These channel modulations contribute to a better understanding of the molecular basis of the effects of neurotransmitters such as ACh which are released by the brainstem arousal system.
The present report introduces PIP 2 and DAG as new elements of signal transduction in the thalamus.
Abstract
The activity of two‐pore domain potassium channels (K 2P ) regulates the excitability and firing modes of thalamocortical (TC) neurons. In particular, the inhibition of two‐pore domain weakly inwardly rectifying K ⁺ channel (TWIK)‐related acid‐sensitive K ⁺ (TASK) channels and TWIK‐related K ⁺ (TREK) channels, as a consequence of the stimulation of muscarinic ACh receptors (MAChRs) which are coupled to phosphoinositide‐specific phospholipase C (PLCβ), induces a shift from burst to tonic firing. By using a whole cell patch‐clamp approach, the contribution of the membrane‐bound second messenger molecules phosphatidylinositol 4,5‐bisphosphate (PIP 2 ) and diacylglycerol (DAG) acting downstream of PLCβ was probed. The standing outward current ( I SO ) was used to monitor the current through TASK and TREK channels in TC neurons. By exploiting different manoeuvres to change the intracellular PIP 2 level in TC neurons, we here show that the scavenging of PIP 2 (by neomycin) results in an increased muscarinic effect on I SO whereas increased availability of PIP 2 (inclusion to the patch pipette; histone‐based carrier) decreased muscarinic signalling. The degree of muscarinic inhibition specifically depends on phosphatidylinositol phosphate (PIP) and PIP 2 but no other phospholipids (phosphatidic acid, phosphatidylserine). The use of specific blockers revealed that PIP 2 is targeting TREK but not TASK channels. Furthermore, we demonstrate that the inhibition of TASK channels is induced by the application of the DAG analogue 1‐oleoyl‐2‐acetyl‐ sn ‐glycerol (OAG). Under current clamp conditions the activation of MAChRs and PLCβ as well as the application of OAG resulted in membrane depolarization, while PIP 2 application via histone carrier induced a hyperpolarization. These results demonstrate a differential role of PIP 2 and DAG in K 2P channel modulation in native neurons which allows a fine‐tuned inhibition of TREK (via PIP 2 depletion) and TASK (via DAG) channels following MAChR stimulation.
... Additional indirect connections also provide for crosstalk between ACh and DA signaling. For example, basal forebrain cholinergic inputs on descending glutamatergic neurons in the PFC provide for "top-down" modulation of VTA DA neurons [40][41][42]. The midbrain DA areas are also innervated by inputs from the extended amygdala that in turn receive cholinergic inputs [43,44], providing a pathway by which stressful events can regulate DA projections to the NAc [45]. ...
Dopamine (DA) signaling in the central nervous system mediates the addictive capacities of multiple commonly abused substances, including cocaine, amphetamine, heroin and nicotine. The firing of DA neurons residing in the ventral tegmental area (VTA), and the release of DA by the projections of these neurons in the nucleus accumbens (NAc), is under tight control by cholinergic signaling mediated by nicotinic acetylcholine (ACh) receptors (nAChRs). The capacity for cholinergic signaling is dictated by the availability and activity of the presynaptic, high-affinity, choline transporter (CHT, SLC5A7) that acquires choline in an activity-dependent matter to sustain ACh synthesis. Here, we present evidence that a constitutive loss of CHT expression, mediated by genetic elimination of one copy of the Slc5a7 gene in mice (CHT+/-), leads to a significant reduction in basal extracellular DA levels in the NAc, as measured by in vivo microdialysis. Moreover, CHT heterozygosity results in blunted DA elevations following systemic nicotine or cocaine administration. These findings reinforce a critical role of ACh signaling capacity in both tonic and drug-modulated DA signaling and argue that genetically-imposed reductions in CHT that lead to diminished DA signaling may lead to poor responses to reinforcing stimuli, possibly contributing to disorders linked to perturbed cholinergic signaling including depression and attention-deficit hyperactivity disorder (ADHD).
... Although the cholinergic neurons are hypothesized to be modulators of tectal activity (Goddard et al. 2007), the information represented in the spatiotemporal pattern of ACh release is largely unknown. In general, the extensive studies of cholinergic modulation in the brain have focused largely on the postsynaptic effect of ACh release (McCormick 1993;Metherate 2004;Lucas-Meunier et al. 2003. Cholinergic Ipc neurons, being visually responsive and reciprocally connected exclusively to the tectum, are an ideal system to study both spatiotemporal pattern of ACh release and its postsynaptic effect on tectal neurons. ...
Feedback pathways are widely present in various sensory systems transmitting time-delayed and partly-processed information from higher to lower visual centers. Although feedback loops are abundant in visual systems, investigations focusing on the mechanisms and roles of feedback in terms of micro-circuitry and system dynamics have been largely ignored. Here, we investigate the cellular, synaptic and circuit level properties of a cholinergic isthmic neuron (Ipc) to understand the role of isthmotectal feedback loop in visual processing of red-ear turtles, Trachemys scripta elegans. Turtle isthmotectal complex contains two distinct nuclei, Ipc and Imc, which interact exclusively with the optic tectum, but are otherwise isolated from other brain areas. The cholinergic Ipc neurons receive topographic glutamatergic inputs from tectal SGP neurons and project back to upper tectal layers in a topographic manner while GABAergic Imc neurons, which also get inputs from the SGP neurons project back non-topographically to both the tectum and Ipc nucleus. We have used an isolated eye-attached whole-brain preparation for our investigations of turtle isthmotectal feedback loop. We have investigated the cellular properties of the Ipc neurons by whole-cell blind-patch recordings and found that all Ipc neurons exhibit tonic firing responses to somatic current injections that are well-modeled by a leaky integrate-and-fire neuron with spike rate adaptation. Further investigations reveal that the optic nerve stimulations generate balanced excitatory and inhibitory synaptic currents in the Ipc neurons. We have also found that synaptic connection between the Imc to Ipc neuron is inhibitory. The visual response properties of the Ipc neurons to a range of computer-generated stimuli are investigated using extracellular recordings. We have found that the Ipc neurons have a localized excitatory receptive field and show stimulus selectivity and stimulus-size tuning. We also investigate lateral interactions in the Ipc neurons in response to multiple stimuli within the visual field. Finally, we quantify the oscillatory bursts observed in Ipc responses under visual stimulations.
... The molecular basis of cholinergic activation divides into rapid effects, which dominate for the first ~ 1 to 10 ms after the onset of acetylcholine release, and prolonged effects, which have delayed onset but persist from ~ 100 ms to 10 s after acetylcholine release (McCormick 1993). On short time-scales, acetylcholine activates ionotropic nicotinic receptors and leads to an augmentation of glutamine-based excitatory transmission, a suppression of GABA-mediated inhibitory transmission (Rovira et al. 1983), and possibly direct excitation of GABA-ergic interneurons (Alkondon et al. 283;Jones and Yakel 1997). ...
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... The electrophysiological actions of cholinergic agonists on neurons have been studied extensively in vitro and, for the most part, are considered excitatory (Halliwell, 1990;Krnjević, 1993;McCormick, 1993). For example, cholinergic stimulation causes a sustained depolarization associated with an increased input resistance (R IN ) and depression of spike frequency adaptation. ...
Cholinergic stimulation of the hippocampal formation results in excitation and/or seizure. We report here, using whole-cell patch-clamp techniques in the hippocampal slice (34–35°C), a cholinergic-dependent slow afterdepolarization (sADP) and long-lasting plateau potential (PP). In the presence of 20 μ m carbachol, action potential firing evoked by weak intracellular current injection elicited an sADP that lasted several seconds. Increased spike firing evoked by stronger depolarizing stimuli resulted in long-duration PPs maintained close to −20 mV. Removal of either Na ⁺ or Ca ²⁺ from the external media, intracellular Ca ²⁺ ([Ca ²⁺ ] i ) chelation with 10 m m bis(2-aminophenoxy)ethane- N,N,N′,N′ -tetra-acetic acid, or the addition of 100 μ m Cd ²⁺ to the perfusate abolished both the sADP and PP. The sADP was depressed and the PP was abolished by either 10 μ m nimodipine or 1 μ m ω-conotoxin, whereas 1.2 μ m tetrodotoxin was ineffective. The involvement of a Na ⁺ /Ca ²⁺ exchanger was minimal because both the sADP and PP persisted after equimolar substitution of 50 m m Li ⁺ for Na ⁺ in the external media or reduction of the bath temperature to 25°C. Finally, in the absence of carbachol the sADP and PP could not be evoked when K ⁺ channels were suppressed, suggesting that depression of K ⁺ conductances alone was not sufficient to unmask the conductance. Based on these data, we propose that a Ca ²⁺ -activated nonselective cation conductance was directly enhanced by muscarinic stimulation. The sADP, therefore, represents activation of this conductance by residual [Ca ²⁺ ] i , whereas the PP represents a novel regenerative event involving the interplay between high-voltage-activated Ca ²⁺ channels and the Ca ²⁺ -activated nonselective cation conductance. This latter mechanism may contribute significantly to ictal depolarizations observed during cholinergic-induced seizures.
... Caudal BF neurons affect electrographic activity via a direct projection to the cortex (305,450,500,1115,1148,1431). Intracellular recordings from cortical neurons in vivo and in vitro have revealed a plethora of cholinergic effects that lead to increased excitability and a facilitation of fast EEG rhythms at the expense of slow oscillations typical of NREM sleep (827,1216). Prominent muscarinic effects include the following: 1) a depolarization of pyramidal neurons via block of a leak potassium conductance (M-current) and activation of mixed cation channels; 2) facilitation of subthreshold oscillations in the beta/gamma range , and 3) blockade of slow afterhyperpolarizations. Nicotinic actions include presynaptic facilitation of glutamate release (443) and depolarization of interneurons (20,579). ...
This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making.
... First, the potassium leakage current is a major constituent of the membrane conductivity and can be affected by neuromodulatory substances such as acetylcholine (ACh) acting via the muscarinic receptor (the I m current) (McCormick, 1992; Wang & McCormick, 1993; Wilson, 1995; cf. McCormick, 1993). Second, synaptic input itself can increase the membrane conductance and thus increase the total electrotonic length of a dendrite (Bernander, Douglas, Martin, & Koch, 1991). ...
... If a change in concentration of a neuromodulator completely alters the temporal structure of the spike train , it would be unlikely that spike timing could serve as a reliable neural code. A major effect of cholinergic modulation on cortical neurons is a reduction in spike frequency adaptation, which is characterized by a shortening of inter-spike-intervals and an increase in neuronal excitability (McCormick 1993;Nicoll 1988) . One obvious consequence of this cholinergic effect is a modification of spike timing ( Fig. 1 A). ...
... We rather hypothesize that the structure of prefrontal networks entrained in oscillatory rhythms changes with age, and, consequently, the effect of the cholinergic input onto these networks also modifies. Initially, ACh acting on mAChRs facilitates the firing of neonatal neurons within gamma-coupled local networks by downregulating several slow potassium currents (McCormick, 1993). With ongoing maturation and refinement of connectivity, the prefrontal networks start to be entrained in continuous theta-gamma rhythms. ...
The cholinergic drive enhances input processing in attentional and mnemonic context by interacting with the activity of prefrontal-hippocampal networks. During development, acetylcholine modulates neuronal proliferation, differentiation, and synaptic plasticity, yet its contribution to the maturation of cognitive processing resulting from early entrainment of neuronal networks in oscillatory rhythms remains widely unknown. Here we show that cholinergic projections growing into the rat prefrontal cortex (PFC) toward the end of the first postnatal week boost the generation of nested gamma oscillations superimposed on discontinuous spindle bursts by acting on functional muscarinic but not nicotinic receptors. Although electrical stimulation of cholinergic nuclei increased the occurrence of nested gamma spindle bursts by 41%, diminishment of the cholinergic input by either blockade of the receptors or chronic immunotoxic lesion had the opposite effect. This activation of locally generated gamma episodes by direct cholinergic projections to the PFC was accompanied by indirect modulation of underlying spindle bursts via cholinergic control of hippocampal theta activity. With ongoing maturation and switch of network activity from discontinuous bursts to continuous theta-gamma rhythms, accumulating cholinergic projections acting on both muscarinic and nicotinic receptors mediated the transition from high-amplitude slow to low-amplitude fast rhythms in the PFC. By exerting multiple actions on the oscillatory entrainment of developing prefrontal-hippocampal networks, the cholinergic input may refine them for later gating processing in executive and mnemonic tasks.
... In the cortex, cholinergic fibers innervate both interneurons and pyramidal cells across all layers (Beaulieu and Somogyi, 1991). ACh exerts excitatory influences upon both cell types, predominantly through muscarinic (M1) receptors and also inhibitory influences upon some interneurons (through M2 receptors) (McCormick, 1993). The influence of the basal forebrain cholinergic neurons upon cortical neurons prevents slow-wave cortical activity and promotes fast cortical activity, particularly in a gamma range (30-60 Hz) (Metherate et al., 1992;Cape and Jones, 2000). ...
This chapter discusses the neurobiology of waking and sleeping. Waking and sleeping are actively generated by neuronal systems distributed through the brainstem and forebrain with different projections, discharge patterns, neurotransmitters, and receptors. Specific ascending systems stimulate cortical activation, characterized by fast, particularly gamma activity that occurs during waking and rapid eye movement (REM) sleep. In addition to glutamatergic neurons of the reticular formation and thalamus, cholinergic pontomesencephalic and basal forebrain neurons are integral components of the ascending activating system. Sleeping is initiated by inhibition of the activating and arousal systems. This inhibition is effected at multiple levels through particular GABAergic neurons which become active during sleep. Neurons in the preoptic area and basal forebrain play a particularly important role in this process. Some become active during slow-wave sleep (SWS), promoting deactivation, and slow-wave activity in the cerebral cortex. Others discharge at progressively increasing rates during SWS and REM sleep, promoting behavioral quiescence, and diminishing muscle tone. Through their projections and inhibitory neurotransmitter, they have the capacity to inhibit the monoaminergic neurons and orexin (Orx)neurons in the brainstem and hypothalamus.
... Although the cholinergic neurons are hypothesized to be modulators of tectal activity ( Goddard et al. 2007), the information represented in the spatiotemporal pattern of ACh release is largely unknown. In general, the extensive studies of cholinergic modulation in the brain have focused largely on the postsynaptic effect of ACh release (McCormick 1993;Lucas-Meunier et al. 2003;Metherate 2004;Lucas-Meunier et al. 2009). Cholinergic Ipc neurons, being visually responsive and reciprocally connected exclusively to the tectum, are an ideal system to study both spatiotemporal pattern of ACh release and its postsynaptic effect on tectal neurons. ...
The optic tectum holds a central position in the tectofugal pathway of non-mammalian species and is reciprocally connected with the nucleus isthmi. Here, we recorded from individual nucleus isthmi pars parvocellularis (Ipc) neurons in the turtle eye-attached whole-brain preparation in response to a range of computer-generated visual stimuli. Ipc neurons responded to a variety of moving or flashing stimuli as long as those stimuli were small. When mapped with a moving spot, the excitatory receptive field was of circular Gaussian shape with an average half-width of less than 3°. We found no evidence for directional sensitivity. For moving spots of varying sizes, the measured Ipc response-size profile was reproduced by the linear Difference-of-Gaussian model, which is consistent with the superposition of a narrow excitatory center and an inhibitory surround. Intracellular Ipc recordings revealed a strong inhibitory connection from the nucleus isthmi pars magnocellularis (Imc), which has the anatomical feature to provide a broad inhibitory projection. The recorded Ipc response properties, together with the modulatory role of the Ipc in tectal visual processing, suggest that the columns of Ipc axon terminals in turtle optic tectum bias tectal visual responses to small dark changing features in visual scenes.
... This tone is in turn modulated in the brainstem and basal forebrain cholinergic arousal centers in a state specific manner by A1Rs [21, 45, 50]. Acetylcholine inhibits slow frequency activity in thalamocortical neurons [13, 37, 64], so inhibition of brainstem cholinergic neurons via A1Rs during SWS allows the expression of slow wave activity. ...
Over the last several decades the idea that adenosine (Ado) plays a role in sleep control was postulated due in large part to pharmacological studies that showed the ability of Ado agonists to induce sleep and Ado antagonists to decrease sleep. A second wave of research involving in vitro cellular analytic approaches and subsequently, the use of neurochemical tools such as microdialysis, identified a population of cells within the brainstem and basal forebrain arousal centers, with activity that is both tightly coupled to thalamocortical activation and under tonic inhibitory control by Ado. Most recently, genetic tools have been used to show that Ado receptors regulate a key aspect of sleep, the slow wave activity expressed during slow wave sleep. This review will briefly introduce some of the phenomenology of sleep and then summarize the effect of Ado levels on sleep, the effect of sleep on Ado levels, and recent experiments using mutant mouse models to characterize the role for Ado in sleep control and end with a discussion of which Ado receptors are involved in such control. When taken together, these various experiments suggest that while Ado does play a role in sleep control, it is a specific role with specific functional implications and it is one of many neurotransmitters and neuromodulators affecting the complex behavior of sleep. Finally, since the majority of adenosine-related experiments in the sleep field have focused on SWS, this review will focus largely on SWS; however, the role of adenosine in REM sleep behavior will be addressed.
Adenosine is a well-known endogenous sleep substance that affects normal sleep-wake patterns through several mechanisms and in various brain locations via A1R or A2AR. Many cells and processes contribute to modulating the extracellular concentration of adenosine at neuronal A1R or A2AR. Current evidence accumulated mainly from rodent studies suggests that A1R and A2AR are differentially involved in regulating sleep. Activation of A2AR in the brain promotes sleep, i.e., these receptors provide sleep gating by activating NAc neurons, whereas activation of A1R modulates the homeostatic aspects of sleep/wake regulation, i.e., these receptors are essential for the expression and resolution of sleep need. Activation of A1R also facilitates sleep by inhibiting wake-active neurons in several brain areas, including cholinergic brainstem and basal forebrain neurons, the lateral hypothalamus containing hypocretin/orexin neurons, and the TMN containing histamine neurons, and disinhibition of sleep-active neurons in the VLPO and anterior hypothalamic areas. The development of selective modulators of A1R and A2AR for use in clinical studies and radioligands for molecular brain imaging may help to elucidate the distinct roles of these receptor subclasses in sleep-wake regulation in humans.
A major challenge in understanding spike-time dependent information encoding in the neural system is the non-linear firing response to inputs of the individual neurons. Hence, quantitative exploration of the putative mechanisms of this non-linear behavior is fundamental to formulating the theory of information transfer in the neural system. The objective of this simulation study was to evaluate and quantify the effect of slowly activating outward membrane current, on the non-linearity in the output of a one-compartment Hodgkin-Huxley styled neuron. To evaluate this effect, the peak conductance of the slow potassium channel (gK-slow) was varied from 0% to 200% of its normal value in steps of 33%. Both cross- and iso-frequency coupling between the input and the output of the simulated neuron was computed using a generalized coherence measure, i.e., n:m coherence. With increasing gK-slow, the amount of sub-harmonic cross-frequency coupling, where the output frequencies (1-8 Hz) are lower than the input frequencies (15-35 Hz), increased progressively whereas no change in iso-frequency coupling was observed. Power spectral and phase-space analysis of the neuronal membrane voltage vs. slow potassium channel activation variable showed that the interaction of the slow channel dynamics with the fast membrane voltage dynamics generates the observed sub-harmonic coupling. This study provides quantitative insights into the role of an important membrane mechanism i.e. the slowly activating outward current in generating non-linearities in the output of a neuron.
Acetylcholine (ACh) is a neurotransmitter widely distributed in the central nervous system (CNS) and peripheral nervous system (PNS). Its role as a neurotransmitter was first elucidated by Dale, who noted that ACh mimicked the effects of parasympathetic nerve stimulation and by Otto Loewi, who demonstrated the vagal release of a substance that slowed heart rate (1–3). More recently ACh in the CNS has been implicated in sensorimotor arousal, attention, sleep regulation, and learning and memory (4–8). Its distribution in the CNS includes the entire cortical mantle and hippocampus innervated by cholinergic neurons of the basal forebrain and the interpeduncular nucleus innervated by the medial habenula. The striatum, nucleus accumbens, and olfactory tubercle each contain cholinergic interneurons (9). The extraction of ACh from these areas in intact preparations historically has been largely via push-pull cannulae and now via microdialysis (10,11). Once extracted from the brain, however, the separation (by high-performance liquid chromatography [HPLC]) and quantification (by electrochemical detection) of ACh presents an unusually difficult problem. Such a difficulty arises first from the extremely rapid hydrolysis of ACh in vivo by ACh esterase and second from the resistance of the ACh molecule to electrochemical oxidation. The first of these problems can be overcome by in vivo application of an esterase inhibitor such as neostigmine, although the use of too high a concentration can dramatically disturb the physiological regulation of the cholinergic system and introduce artifactual experimental results (12–14).
The hypothesis of distinct memory codes proposes that entities belonging to global categories as verbal and spatial representations, or to more specific categories as faces, objects, living or non-living entities, are stored and reactivated in functionally separate memory partitions. In this chapter we will summarize evidence which supports this principle of code-specificity in memory. First, we will briefly review the empirical roots which can be found in Cognitive Psychology, Experimental Neuropsychology, and Clinical Neuropsychology. We will then outline a general neuroscientific theory which explains why code-specific memory representations do most likely exist, and finally, in the main part of the chapter, we will give an overview over recent brain findings that are highly consistent with the idea of code specific storage and retrieval within topographically distinct neural networks.
The capability of the central nervous system (CNS) to adapt its functional and structural organization to current requirements is known as neural plasticity. Such changes can be examined at different organizational levels of the CNS; changes at the molecular-, synaptic-, neural-, system-, and behavioral level are mutually dependent (Shaw & McEachern, 2001). Plastic changes are triggered by learning, e.g., perceptual and motor training and by injuries, e.g., a deafferentation of parts or of all afferents of a sensory system. Moreover, the capacity to change is a characteristic feature of the CNS throughout life although there are qualitative and quantitative differences between developmental and adult plasticity. This chapter reports major findings on training- and lesion-induced plasticity. Results from animal and human research in the somatosensory, auditory, visual and motor system are reviewed and the possibly mechanisms underlying brain plasticity are discussed. Moreover, possible differences between developmental and adult plasticity are considered.
The phase response curve (PRC) reflects the dynamics of the interplay between diverse intrinsic conductances that lead to spike generation. PRCs measure the spike time shift caused by perturbations of the membrane potential as a function of the phase of the spike cycle of a neuron. A purely positive PRC is a signature of type I (saddle-node) dynamics while type II (subcritical Hopf dynamics) yield a biphasic PRC with both negative and positive lobes. Previous computational work hypothesized that cholinergic modulation of M-type potassium current can switch a neuron with type II dynamics to type I dynamics. We recorded from layer 2/3 pyramidal neurons in cortical slices, and found that cholinergic action, consistent with downregulation of slow voltage-dependent potassium currents such as the M-current, indeed changed the PRC from type II to type I. We then explored the potential specific K-current-dependent mechanisms for this switch using a series of computational models. In all of these models, we show that a decrease in spike-frequency adaptation due to downregulation of the M-current is associated with the switch in PRC type. Interestingly spike-dependent I-AHP is downregulated at lower Ach concentrations than the M-current. Our simulations showed that type II nature of the PRC is amplified by low Ach level, while the PRC became type I at high Ach concentrations. We further explored the spatial aspects of Ach modulation in a compartmental model. This work suggests that cholinergic modulation of slow potassium currents may shape neuronal responding between “resonator” to “integrator.”
In addition to innervating the cerebral cortex, basal forebrain cholinergic (BFc) neurons send a dense projection to the basolateral nucleus of the amygdala (BLA). In this study, we investigated the effect of near physiological acetylcholine release on BLA neurons using optogenetic tools and in vitro patch-clamp recordings. Adult transgenic mice expressing cre-recombinase under the choline acetyltransferase promoter were used to selectively transduce BFc neurons with channelrhodopsin-2 and a reporter through the injection of an adeno-associated virus. Light-induced stimulation of BFc axons produced different effects depending on the BLA cell type. In late-firing interneurons, BFc inputs elicited fast nicotinic EPSPs. In contrast, no response could be detected in fast-spiking interneurons. In principal BLA neurons, two different effects were elicited depending on their activity level. When principal BLA neurons were quiescent or made to fire at low rates by depolarizing current injection, light-induced activation of BFc axons elicited muscarinic IPSPs. In contrast, with stronger depolarizing currents, eliciting firing above ∼6-8 Hz, these muscarinic IPSPs lost their efficacy because stimulation of BFc inputs prolonged current-evoked afterdepolarizations. All the effects observed in principal neurons were dependent on muscarinic receptors type 1, engaging different intracellular mechanisms in a state-dependent manner. Overall, our results suggest that acetylcholine enhances the signal-to-noise ratio in principal BLA neurons. Moreover, the cholinergic engagement of afterdepolarizations may contribute to the formation of stimulus associations during fear-conditioning tasks where the timing of conditioned and unconditioned stimuli is not optimal for the induction of synaptic plasticity.
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The natural world presents us with a rich and ever-changing sensory landscape containing diverse stimuli that constantly compete for representation in the brain. When the brain selects a stimulus as the highest priority for attention, it differentially enhances the representation of the selected, “target” stimulus and suppresses the processing of other, distracting stimuli. A stimulus may be selected for attention while it is still present in the visual scene (predictive selection) or after it has vanished (post hoc selection). We present a biologically inspired computational model that accounts for the prioritized processing of information about targets that are selected for attention either predictively or post hoc. Central to the model is the neurobiological mechanism of “selective disinhibition” – the selective suppression of inhibition of the representation of the target stimulus. We demonstrate that this mechanism explains major neurophysiological hallmarks of selective attention, including multiplicative neural gain, increased inter-trial reliability (decreased variability), and reduced noise correlations. The same mechanism also reproduces key behavioral hallmarks associated with target-distracter interactions. Selective disinhibition exhibits several distinguishing and advantageous features over alternative mechanisms for implementing target selection, and is capable of explaining the effects of selective attention over a broad range of real-world conditions, involving both predictive and post hoc biasing of sensory competition and decisions.
Distributed within the laterodorsal tegmental and pedunculopontine tegmental nuclei (LDT and PPT), cholinergic neurons in the pontomesencephalic tegmentum have long been thought to play a critical role in stimulating cortical activation during waking (W) and paradoxical sleep (PS, also called REM sleep), yet also in promoting PS with muscle atonia. However, the discharge profile and thus precise roles of the cholinergic neurons have remained uncertain because they lie intermingled with GABAergic and glutamatergic neurons, which might also assume these roles. By applying juxtacellular recording and labeling in naturally sleeping-waking, head-fixed rats, we investigated the discharge profiles of histochemically identified cholinergic, GABAergic, and glutamatergic neurons in the LDT, SubLDT, and adjoining medial part of the PPT (MPPT) in relation to sleep-wake states, cortical activity, and muscle tone. We found that all cholinergic neurons were maximally active during W and PS in positive correlation with fast (γ) cortical activity, as "W/PS-max active neurons." Like cholinergic neurons, many GABAergic and glutamatergic neurons were also "W/PS-max active." Other GABAergic and glutamatergic neurons were "PS-max active," being minimally active during W and maximally active during PS in negative correlation with muscle tone. Conversely, some glutamatergic neurons were "W-max active," being maximally active during W and minimally active during PS in positive correlation with muscle tone. Through different discharge profiles, the cholinergic, GABAergic, and glutamatergic neurons of the LDT, SubLDT, and MPPT thus appear to play distinct roles in promoting W and PS with cortical activation, PS with muscle atonia, or W with muscle tone.
This chapter discusses the cholinergic hypothesis of Alzheimer's disease (AD) through a computational investigation of the neuromodulation of single cells and networks by acetylcholine in the CA3 region of the hippocampus. The chapter discusses the results that provide insight into the regulatory role of acetylcholine in learning, and recall and suggest novel mechanisms for the decline in memory function that accompanies AD. The cholinergic hypothesis of AD initially arose from the observed AD-related decreases in the activity of choline aceiyltransferase (ChAT), the enzyme responsible for synthesizing acetylcholine. This observation is made in post-mortem tissue but has since been confirmed in antemortem biopsies. This theory, tying low levels of acetylcholine to cognitive impairment, gained support from the observed decreases in choline uptake, decreases in ACh release, and the death of subcortical cholinergic neurons and the disappearance of cholinergic varicosities in the early stages of AD. This hypothesis led to the recent clinical trials of a variety of acetylcholinesterase (AChE) inhibitors currently the first-line pharmacological approach to treating AD.
The neocortex, evolutionarily the most recent part of the brain, contains maps that represent sensory space. In a report in this issue, [Kilgard and Merzenich][1] show that the auditory map of the rat can be coaxed to change dramatically by stimulating a nucleus in the basal forebrain. In her commentary, Juliano discusses this work in the context of what is known about long- and short-term regulation of maps in the brain.
[1]: http://www.sciencemag.org/cgi/content/short/279/5357/1714
Objective:
Deep brain stimulation (DBS) is a therapeutically effective neurosurgical method originally applied in movement disorders. Over time, the application of DBS has increasingly been considered as a therapeutic option for several neuropsychiatric disorders, including Gilles de la Tourette syndrome, obsessive compulsive disorder, major depression and addiction. Latest research suggests beneficial effects of DBS in Alzheimer dementia (AD). Because of the high prevalence and the considerable burden of the disease, we endeavored to discuss and reveal the challenges of DBS in AD.
Methods:
Recent literature on the pathophysiology of AD, including translational data and human studies, has been studied to generate a fundamental hypothesis regarding the effects of electrical stimulation on cognition and to facilitate our ongoing pilot study regarding DBS of the nucleus basalis Meynert (NBM) in patients with AD.
Results:
It is hypothesized that DBS in the nucleus basalis Meynert could probably improve or at least stabilize memory and cognitive functioning in patients with AD by facilitating neural oscillations and by enhancing the synthesis of nerve growth factors.
Conclusions:
Considering the large number of patients suffering from AD, there is a great need for novel and effective treatment methods. Our research provides insights into the theoretical background of DBS in AD. Providing that our hypothesis will be validated by our ongoing pilot study, DBS could be an opportunity in the treatment of AD.
We describe a computational method for assessing functional connectivity in sensory neuronal networks. The method, which we
term cross-trial correlation, can be applied to signals representing local field potentials (LFPs) evoked by sensory stimulations and utilizes their trial-to-trial
variability. A set of single trial samples of a given post-stimulus latency from consecutive evoked potentials (EPs) recorded
at a given site is correlated with such sets for all other latencies and recording sites. The results of this computation
reveal how neuronal activities at various sites and latencies correspond to activation of other sites at other latencies.
The method was used to investigate the functional connectivity of thalamo-cortical network of somatosensory system in behaving
rats at two levels of alertness: habituated and aroused. We analyzed potentials evoked by vibrissal deflections recorded simultaneously
from the ventrobasal thalamus and barrel cortex. The cross-trial correlation analysis applied to the early post-stimulus period
(<25ms) showed that the magnitude of the population spike recorded in the thalamus at 5ms post-stimulus correlated with
the cortical activation at 6–13ms post-stimulus. This correlation value was reduced at 6–9ms, i.e. at early postsynaptic
cortical response, with increased level of the animals’ arousal. Similarly, the aroused state diminished positive thalamo-cortical
correlation for subsequent early EP waves, whereas the efficacy of an indirect cortico-fugal inhibition (over 15ms) did not
change significantly. Thus we were able to characterize the state related changes of functional connections within the thalamo-cortical
network of behaving animals.
KeywordsLFP-Awake rat-Vibrissae-barrel system-Functional connectivity
1.1. Several lines of evidence support the notion of cholinergicity of cognition and organism-environment interaction: a) Certain central pathways which were amply demonstrated as cholinergic in nature were also shown as significant for cognition and related processes; this is indicated by lesion experiments in animals and related evidence collected in man which includes that obtained in SDAT. b) Cholinergic agonists evoke a specific EEG alerting and hippocampal theta patterns that were shown to be the EEG counterparts of learning. c) The REM sleep reflects significant cholinergic correlates, and this phenomenology relates to the EEG components of cognition. d) Cholinergic agonists facilitate and cholinergic antagonists disrupt animal learning; in fact, beneficial effects were obtained with cholinergic agonists in animal models specifically designed to reflect impaired animal-environment interaction. e) Trophic factors restore cognition in lesioned animals and may exhibit similar action in human subjects suffering from cholinergic deficit.2.2. While many of these effects show that the cholinergic phenomena underlie cognitive facilitation and specific alerting, certain depressive symptoms are evoked in man and animals by muscarinic agonists.3.3. Altogether, it is speculated that, overall the central cholinergic function in awaken man and animals represents a cholinergic syndrome which relates to REM sleep and which exhibits a number of characteristic EEG, functional and behavioral phenomena. This syndrome is referred to as CANMB and its normal function underlies appropriate animal-organism interaction.
The paper gives a brief overview of five experimental approaches in which memory processes were studied by means of event-related brain potentials (ERPs). Some of the results were already published in English (Study 1), while others are new and will be reported in greater length as full paper elsewhere (Studies 2, 3, 4, and 5). Study 1 revealed that retrieval of information from episodic long-term memory is accompanied by a systematic slow negative potential. The topography of this slow wave depends on the quality of the reactivated information (spatial vs. verbal), and its amplitude reflects the difficulty of the retrieval process. In experiment 2 ERPs were recorded while subjects acquired either explicit or implicit knowledge about a sequential stimulus-response pattern. The data suggest that explicit learners who posses verbalizable knowledge about sequential dependencies have formed both perceptual and motor representations, while implicit learners have formed motor representations only. In study 3 fact retrieval in mental arithmetic was activated by a verification task. Incongruent solutions evoked an arithmetic N400-effect whose amplitude varied with the associative distance between an expected and an actually perceived solution to a multiplication problem. In study 4 ERPs were recorded during mental rotation tasks. A set of experiments revealed that mental rotation is always accompanied by a systematic negative variation over the parietal cortex. The amplitude of this "rotation specific negativity" increases with an increasing angular disparity between a perceived sign and its normal upright template. It was shown that this negativity is functionally distinct from a P300-complex which is often superimposed on it within the same latency window. Finally, study 5 examined ERPs in a sentence reading task in which grammatically legal but infrequent sentence constructions had to be processed. A left-anterior negativity was observed whenever an explicit case marker (the definite article in German) signalled a nominal phrase at a noncanonical position. The LAN phenomenon appears to be a manifestation of a syntax processor which performes a first-pass formal analysis of a sentence and which possibly allocates working memory resources whenever a word cannot be assigned immediately to an expected propositional role.
The functional properties, ionic basis, and possible convergence and interaction of postsynaptic actions mediated by muscarinic and alpha 1-adrenergic receptors were examined in cat and guinea pig dorsal lateral geniculate (LGNd) neurons maintained in thalamic slices in vitro. The possible involvement of GTP-binding proteins was also examined. Extracellular recordings from cat LGNd revealed the presence of two subpopulations of neurons. The most prevalent generated rhythmic high-frequency (300-500 Hz) bursts of two to six action potentials each, with an interburst frequency of 1-3 Hz. Intracellular recordings revealed that this activity is typical of thalamocortical relay cells in the apparent absence of neuromodulatory input. Application of ACh or noradrenaline (NA) to rhythmically oscillating neurons in the cat LGNd resulted in cessation of this activity followed by the appearance of single spike firing. Intracellular recordings revealed that this change in firing mode was associated with a depolarization of the neuron out of the range of intrinsic rhythmic oscillation and into or near the single spike firing mode. The voltage characteristics of the current underlying the cholinergic and noradrenergic slow depolarization were investigated in guinea pig LGNd neurons. Application of the muscarinic agonist acetyl-beta-methylcholine (MCh) to presumed relay neurons resulted in a hyperpolarization due to the activation of an outward K+ current. This response was followed by a slow depolarization due to reduction of a relatively non-voltage-dependent potassium current distinct from IM and IAHP. Application of NA resulted in a slow depolarization that was also associated with reduction of this relatively linear K+ current. The MCh- and NA-induced slow depolarizations displayed the property of occlusion, indicating convergence of action. However, these responses were mediated by pharmacologically distinct receptors since the MCh-induced reduction in K+ current was blocked by scopolamine while that induced by NA was blocked by the alpha 1-adrenoceptor antagonist prazosin. Intracellular diffusion of GTP-gamma-S resulted in the inward current responses to NA and MCh being irreversible, suggesting the possible involvement of a G-protein. Prior exposure to pertussis toxin did not affect the inward current response to NA and MCh, while the outward K+ current responses induced by application of MCh or the GABAB agonist baclofen were blocked. These results reveal that activation of muscarinic or alpha 1-adrenergic postsynaptic receptors in the LGNd result in a shift in firing mode from rhythmic oscillation to tonic single spike activity through a decrease in a relatively linear K+ current mediated through a pertussis toxin-insensitive G-protein.(ABSTRACT TRUNCATED AT 400 WORDS)
Sympathetic neurons dissociated from the superior cervical ganglion of 2-day-old rats were studied by whole-cell patch clamp and by fura-2 measurements of the cytosolic free Ca2+ concentration, [Ca2+]i. Step depolarizations in the presence of tetrodotoxin and hexamethonium triggered two Ca2+ currents that differed in the voltage dependence of activation and kinetics of inactivation. These currents resemble the L and N currents previously described in chicken sensory neurons [Nowycky, M. C., Fox, A. P. & Tsien, R. W. (1985) Nature (London) 316, 440-442]. Treatment with acetylcholine resulted in the rapid (within seconds), selective, and reversible inhibition of the rapidly inactivated, N-type current, whereas the long-lasting L-type current remained unaffected. The high sensitivity to blocker drugs (atropine, pirenzepine) indicated that this effect of acetylcholine was due to a muscarinic M1 receptor. Intracellular perfusion with nonhydrolyzable guanine nucleotide analogs or pretreatment of the neurons with pertussis toxin had profound effects on the Ca2+ current modulation. Guanosine 5'-[gamma-thio]triphosphate caused the disappearance of the N-type current (an effect akin to that of acetylcholine, but irreversible), whereas guanosine 5'-[beta-thio]diphosphate and pertussis toxin pretreatment prevented the acetylcholine-induced inhibition. In contrast, cAMP, applied intracellularly together with 3-isobutyl-1-methylxanthine, as well as activators and inhibitors of protein kinase C, were without effect. Acetylcholine caused shortening of action potentials in neurons treated with tetraethylammonium to partially block K+ channels. Moreover, when applied to neurons loaded with the fluorescent indicator fura-2, acetylcholine failed to appreciably modify [Ca2+]i at rest but caused a partial blunting of the initial [Ca2+]i peak induced by depolarization with high K+. This effect was blocked by muscarinic antagonists and pertussis toxin and was unaffected by protein kinase activators. Thus, muscarinic modulation of the N-type Ca2+ channels appears to be mediated by a pertussis toxin-sensitive guanine nucleotide-binding protein and independent of both cAMP-dependent protein kinase and protein kinase C.
The postsynaptic actions of acetylcholine, adenosine, gamma-aminobutyric acid, histamine, norepinephrine, and serotonin were analyzed in human cortical pyramidal cells maintained in vitro. The actions of these six putative neurotransmitters converged onto three distinct potassium currents. Application of acetylcholine, histamine, norepinephrine, or serotonin all increased spiking by reducing spike-frequency adaptation, in part by reducing the current that underlies the slow after hyperpolarization. In addition, application of muscarinic receptor agonists to all neurons or of serotonin to middle-layer cells substantially reduced or blocked the M-current (a K+ current that is voltage and time dependent). Inhibition of neuronal firing was elicited by adenosine, baclofen (a gamma-aminobutyric acid type B receptor agonist), or serotonin and appeared to be due to an increase in the same potassium current by all three agents. These data reveal that individual neuronal currents in the human cerebral cortex are under the control of several putative neurotransmitters and that each neurotransmitter may exhibit more than one postsynaptic action. The specific anatomical connections of these various neurotransmitter systems, as well as their heterogeneous distribution of postsynaptic receptors and responses, allows each to make a specific contribution to the modulation of cortical activity.
Healthy bullfrog sympathetic ganglion cells often show a two-component afterhyperpolarization (AHP). Both components can be reduced or abolished by adding Ca-channel blockers or by removing external Ca. Application of a single electrode "hybrid clamp"--i.e., switching from current- to voltage-clamp at the peak of the AHP, reveals that the slow AHP component is generated by a small, slow, monotonically decaying outward current, which we call IAHP. IAHP is blocked by Ca-removal or by apamin and is a pure K current. It is slightly sensitive to muscarine and to tetraethylammonium ion but is much less so than muscarine-sensitive (IM) and fast Ca-dependent (IC) K currents. It also can be recorded in dual-electrode voltage-clamp experiments, where it is seen as a slow, small component of the outward tail current that follows brief depolarizations to 0 mV or beyond. IC is seen as an early, fast, large component of the same tail current. Both components are blocked by Ca removal, but only the IC component is blocked by low doses of tetraethylammonium ion. Thus, bullfrog ganglion cells exhibit two quite distinct Ca-dependent K currents, which differ in size, voltage-sensitivity, kinetics, and pharmacology. These two currents also play quite separate roles in shaping the action potential.
1. The mechanisms of action of acetylcholine (ACh) in the medial (m.g.n.) and dorsal lateral geniculate (l.g.n.d.) nuclei were investigated using intracellular recordings techniques in guinea-pig and cat in vitro thalamic slices. 2. Application of ACh to neurones in guinea-pig geniculate nuclei resulted in a hyperpolarization in all neurones followed by a slow depolarization in 52% of l.g.n.d. and 46% of m.g.n. neurones. Neither the hyperpolarization nor the slow depolarization were eliminated by blockade of synaptic transmission and both were activated by acetyl-beta-methylcholine and DL-muscarine and blocked by scopolamine, indicating that these responses are mediated by direct activation of muscarinic receptors on the cells studied. 3. The ACh-induced hyperpolarization was associated with an increase in apparent input conductance (Gi) of 4-13 nS. The reversal potential of the ACh-induced hyperpolarization varied in a Nernstian manner with changes in extracellular [K+] and was greatly reduced by bath application of the K+ antagonist Ba2+ or intracellular injection of Cs+. These findings show that the muscarinic hyperpolarization is mediated by an increase in K+ conductance. 4. The ACh-induced slow depolarization was associated with a decrease in Gi of 2-15 nS, had an extrapolated reversal potential near EK, and was sensitive to [K+]o, indicating that this response is due to a decrease in K+ conductance. 5. In contrast to effects on guinea-pig geniculate neurones, applications of ACh to cat l.g.n.d. and m.g.n. cells resulted in a rapid depolarization in nearly all cells, followed in some neurones by a hyperpolarization and/or a slow depolarization. The rapid excitatory response was associated with an increase in membrane conductance, had an estimated reversal potential of -49 to -4 mV and may be mediated by nicotinic receptors. The hyperpolarization and slow depolarization were similar to those of the guinea-pig in that they were associated with an increase and decrease, respectively, of Gi, and were mediated by muscarinic receptors. 6. The muscarinic hyperpolarization interacted with the intrinsic properties of the thalamic neurones to inhibit single-spike activity while promoting the occurrence of burst discharges. The muscarinic slow depolarization had the opposite effect; it brought the membrane potential into the range where burst firing was blocked and single-spike firing predominated. Depending upon the membrane potential, the rapid excitatory response of cat geniculate neurones could activate either a burst or a train of action potentials.(ABSTRACT TRUNCATED AT 400 WORDS)
The mechanisms of action of acetylcholine (ACh) in the guinea-pig neocortex were investigated using intracellular recordings from layer V pyramidal cells of the anterior cingulate cortical slice. At resting membrane potential (Vm = -80 to -70 mV), ACh application resulted in a barrage of excitatory and inhibitory post-synaptic potentials (p.s.p.s) associated with a decrease in apparent input resistance (Ri). ACh, applied to pyramidal neurones depolarized to just below firing threshold (Vm = -65 to -55 mV), produced a short-latency hyperpolarization concomitant with p.s.p.s and a decrease in Ri, followed by a long-lasting (10 to greater than 60 s) depolarization and action potential generation. Both of these responses were also found in presumed pyramidal neurones of other cortical regions (sensorimotor and visual) and were blocked by muscarinic, but not nicotinic, antagonists. The ACh-induced hyperpolarization possessed an average reversal potential of -75.8 mV, similar to that for the hyperpolarizing response to gamma-aminobutyric acid (GABA; -72.4 mV) and for the i.p.s.p. generated by orthodromic stimulation (-69.6 mV). This cholinergic inhibitory response could be elicited by ACh applications at significantly greater distance from the cell than the slow depolarizing response. Blockade of GABAergic synaptic transmission with solution containing Mn2+ and low Ca2+, or by local application of tetrodotoxin (TTX), bicuculline or picrotoxin, abolished the ACh-induced inhibitory response but not the slow excitatory response. In TTX (or Mn2+, low Ca2+) the slow excitatory response possessed a minimum onset latency of 250 ms and was associated with a voltage-dependent increase in Ri. Application of ACh caused short-latency excitation associated with a decrease in Ri in eight neurones. The time course of this excitation was similar to that of the inhibition seen in pyramidal neurones. Seven of these neurones had action potentials with unusually brief durations, indicating that they were probably non-pyramidal cells. ACh blocked the slow after-hyperpolarization (a.h.p.) following a train of action potentials, occasionally reduced orthodromically evoked p.s.p.s, and had no effect on the width or maximum rate of rise or fall of the action potential. It is concluded that cholinergic inhibition of pyramidal neurones is mediated through a rapid muscarinic excitation of non-pyramidal cells, resulting in the release of GABA. In pyramidal cells ACh causes a relatively slow blockade of both a voltage-dependent hyperpolarizing conductance (M-current) which is most active at depolarized membrane potentials, and the Ca2+-activated K+ conductance underlying the a.h.p.(ABSTRACT TRUNCATED AT 400 WORDS)
We have used an in situ RNA X RNA hybridization technique to determine, in the central nervous systems of the mouse and rat, the distribution of RNA homologous to cDNA clones encoding the alpha subunit of a putative neural nicotinic acetylcholine receptor and the alpha subunit of the muscle nicotinic acetylcholine receptor. Hybridization of the neural alpha-subunit probe was strongest in the medial habenula but was also detected consistently in the compact part of the substantia nigra and ventral tegmental area, in the neocortex, and in certain parts of the thalamus and hypothalamus. The in situ hybridization technique makes it possible to compile a map of brain regions containing cell bodies expressing RNA coding for a specific receptor type and subsequently to apply the techniques of molecular biology to study these brain receptors.
The transmission of visual information from retina to cortex through the dorsal lateral geniculate nucleus (LGNd) is controlled by non-retinal inputs. Enhanced visually evoked responses in cat LGNd relay cells during periods of increased alertness have been attributed in large part to increased rate of acetylcholine (ACh) release by fibres ascending from the brainstem reticular formation. ACh can modulate geniculate visual responses in vivo, but comparatively little is known about the underlying ionic mechanisms of these cholinergic actions. Although direct excitation of LGNd relay neurons has been shown in vitro, the situation is complicated because cholinergic axons form numerous and complex synapses not only with relay cells, but also with inhibitory interneurons, and electrical activation of the brainstem cholinergic neurons reduces inhibitory postsynaptic potentials in the LGNd. We report here that morphologically characterized interneurons in the cat LGNd possess distinctive electrophysiological properties in comparison with those of relay cells and are inhibited by ACh through a muscarinic receptor-mediated increase in potassium conductance. Together the direct excitation of relay cells and inhibition of intrageniculate interneurons allow the ascending cholinergic system to exert a powerful facilitatory influence over the transfer of visual information to the cerebral cortex.
The actions of ACh in the medial habenular nucleus (MHb) were investigated using extra- and intracellular recording techniques in guinea pig thalamic slice maintained in vitro. Applications of ACh to MHb neurons resulted in rapid excitation followed by inhibition. Neither of these responses was abolished by blockade of synaptic transmission, indicating that they are consequences of ACh action directly on MHb cells. Local applications of the nicotinic agonists nicotine and cytisine caused long-lasting excitation, while applications of another nicotinic agonist, 1,1-dimethyl-4-phenylpiperazinium caused both the excitatory and inhibitory responses. Applications of the muscarinic agonists DL-muscarine and acetyl-beta-methylcholine did not consistently cause either the excitatory or inhibitory response. Adding the nicotinic antagonist hexamethonium to the bathing medium blocked both the excitatory and inhibitory ACh responses, while addition of the muscarinic antagonists atropine or scopolamine had no effect. These results indicate that the effects of ACh on MHb neurons are mediated by nicotinic receptors. Intracellular recordings revealed that ACh or nicotine cause an increase in membrane conductance associated with depolarizations that had an average reversal potential of -16 to -11 mV. These results indicate that the ACh-induced excitation is due to an increase in membrane cation conductance. The inhibitory response that follows ACh-induced depolarization and repetitive firing was associated with a hyperpolarization and an increase in membrane conductance. Similar postexcitatory inhibition could also be elicited by direct depolarization or by applications of glutamate, indicating that the hyperpolarizing response to ACh may be an endogenous postexcitatory potential that is not directly coupled to activation of nicotinic receptors. These results suggest that cholinergic transmission in the MHb may be largely of the nicotinic type. This nucleus may be of one of the major regions of the nervous system through which nicotine mediates its central effects.
A slow muscarinic EPSP, accompanied by an increase in membrane input resistance, can be elicited in hippocampal CA1 pyramidal cells in vitro by electrical stimulation of cholinergic afferents in the slice preparation. Associated with the slow EPSP is a blockade of calcium-activated potassium afterhyperpolarizations (AHPs) (Cole and Nicoll, 1984a). In this study a single-electrode voltage clamp was used to examine the currents affected by activation of muscarinic receptors, using either bath application of carbachol or electrical stimulation of the cholinergic afferents. The 3 main findings of this study are that (1) of the 2 calcium-activated potassium currents (termed IAHP and IC) in hippocampal pyramidal cells, only IAHP is sensitive to carbachol; (2) IAHP is approximately 10-fold more sensitive to carbachol than is another muscarine-sensitive current, IM; and (3) neither blockade of IAHP nor of IM can account for the production of the slow EPSP. Rather, the slow EPSP appears to be generated by the blockade of a nonvoltage-dependent, resting potassium current. We propose that the muscarinic blockade of IAHP, which largely accounts for spike frequency adaptation, is primarily involved in enhancing action potential discharge to depolarizing stimuli, while the slow EPSP acts directly to cause action potential discharge.
The action of acetylcholine at muscarinic receptors on excitable tissues has profoundly influenced the development of ideas on chemical transmission. Much of the early progress was the result of the availability and long historical use of belladonna alkaloids. In experiments never published, carried out in 1906, Dixon showed that atropine blocked the inhibitory effect on the exposed frog heart of an extract partially purified from the heart of a dog under vagal inhibition (Dale, 1934). In 1921, Loewi of Graz in Austria reported his experiments on the effects of vagusstoff, providing convincing evidence for chemical transmission. However, even in those long ago days, it was clear to some that the muscarinic actions of esters of choline were not uniformly inhibitory; Sir Henry Dale was “struck by the remarkable fidelity with which [acetylcholine] reproduced the various effects of parasympathetic nerves, inhibitor on some organs and augmentor on others” (Dale, 1934).
This review concerns the relationship between electrophysiological activity of the brain and the central cholinergic system. This dipole may be construed in a sense so broad as to be beyond the space limitations of this article; thus, further defining is necessary. Electrophysiological activity to be reviewed here is generated by neuronal populations rather than single neurons, as it involves cholinergically mediated changes in ongoing electrical activity of neuronal populations referred to as electroencephalograph (EEG), electrocorticogram (ECoG), etc. Another major response of neuronal populations, which is also the subject of this review is the compound potential evoked by peripheral or brain stimulation (EP). On the other hand, while the EEG and ECoG are generated by the summation of individual postsynaptic potentials and related phenomena, the pertinent unitary mechanisms whether concerning noncholinergic or cholinoceptive and cholinergic neurons cannot be reviewed in the present context.
It is traditionally believed that cerebral activation (the presence of low voltage fast electrical activity in the neocortex and rhythmical slow activity in the hippocampus) is correlated with arousal, while deactivation (the presence of large amplitude irregular slow waves or spindles in both the neocortex and the hippocampus) is correlated with sleep or coma. However, since there are many exceptions, these generalizations have only limited validity. Activated patterns occur in normal sleep (active or paradoxical sleep) and during states of anesthesia and coma. Deactivated patterns occur, at times, during normal waking, or during behavior in awake animals treated with atropinic drugs. Also, the fact that patterns characteristic of sleep, arousal, and waking behavior continue in decorticate animals indicates that reticulo-cortical mechanisms are not essential for these aspects of behavior.
These puzzles have been largely resolved by recent research indicating that there are two different kinds of input from the reticular activating system to the hippocampus and neocortex. One input is probably cholinergic; it may play a role in stimulus control of behavior. The second input is noncholinergic and appears to be related to motor activity; movement-related input to the neocortex may be dependent on a trace amine.
Reticulo-cortical systems are not related to arousal in the traditional sense, but may play a role in the control of adaptive behavior by influencing the activity of the cerebral cortex, which in turn exerts control over subcortical circuits that co-ordinate muscle activity to produce behavior.
With the exception of olfactory signals, all sensory information is relayed through thalamic nuclei before it reaches the corresponding cortical areas for further processing. Because of this key position in the afferent pathway of sensory systems, considerable effort has been devoted in the past to the analysis of the thalamic relay nuclei. These studies revealed an unexpectedly high degree of complexity in the connectivity and operations of these nuclei that was incompatible with the hypothesis of a simple relay function. The electrophysiological investigation of input-output relations revealed extensive processing of afferent activity at the thalamic level. Morphological studies showed an extremely complicated intrinsic circuitry that is still not fully understood in its functional implications. The most intriguing discovery was that the transmission properties of relay nuclei are controlled to a considerable extent by corticofugal and ascending reticular pathways.
The possible involvement of cholinergic mechanisms and of GABA in the modulation and generation of ponto geniculo occipital (PGO) waves was studied using PGO waves induced by the benzoquinolizine derivative, Ro 4-1284 (= PGO1284), and by p chlorophenyl alanine (= PGO(PCPA)), and continuously recorded and counted in the lateral geniculate bodies of unanaesthetized immobilized cats. Atropine had no significant effect on PGO1284 but markedly depressed the density of PGO(PCPA); this effect of atropine was absent when the synthesis of noradrenaline (NA) was inhibited in addition to that of 5 hydroxytryptamine (5 HT). Arecoline and eserine at a low dose increased the density of PGO(PCPA). Both the stimulation of nicotinic receptors by nicotine and their blockade by mecamylamine reduced the amplitude of PGO1284 and PGO(PCPA). Eserine, 0.3 mg/kg i.v., had a similar effect. GABA injected into a lateral brain ventricle augmented the density of PGO(PCPA) but not of PGO1284. Increasing the level of endogenous GABA by amino oxyacetic acid (AOAA) and by hydroxylamine affected PGO waves like GABA. Bicuculline tended to decrease the density of PGO(PCPA). Chlordiazepoxide increased the density of PGO1284 and, more markedly, that of PGO(PCPA). The latter effect was prevented by atropine and by lesions placed in the amygdala, the septum and the medial forebrain bundle several days prior to the acute experiment.
We have assessed the potency of a range of agonists and antagonists on the muscarinic receptor responsible for inhibiting the Ca‐current ( I Ca ) in NG 108–15 hybrid cells.
Acetylcholine (ACh), oxotremorine‐M and carbachol were potent ‘full’ agonists (EC 50 values were 0.11 μ m , 0.14 μ m and 2 μ m , respectively). Maximum inhibition of peak high‐threshold I Ca by these agonists was 39.5%. (±)‐Muscarine, methylfurmethide and arecaidine propargyl ester (APE) were ‘partial’ agonists, with EC 50 values of 0.54 μ m , 0.84 μ m and 0.1 μ m , respectively.
Atropine, pirenzepine and himbacine were potent antagonists of muscarinic inhibition of I Ca , with apparent pK B values of 9.8, 7.74 and 8.83, respectively. Methoctramine was relatively weak (pK B = 7.63). Atropine and pirenzepine depressed maximum responses to agonists, probably because these antagonists have relatively slow dissociation rates.
The characteristic pharmacological profile found for the M 4 receptors in these functional experiments (himbacine high affinity, pirenzepine moderate to high affinity, methoctramine low affinity) corresponds well with data from earlier binding experiments (Lazareno et al. , 1990). Since mRNA hybridising to probes for the m4 receptor genotype can be detected in these cells, it is suggested that these pharmacological characteristics identify the equivalent expressed receptor subtype M 4 .
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Nicotinic acetylcholine receptors found in the peripheral and central nervous system differ from those found at the neuromuscular junction. Recently we isolated a cDNA clone encoding the alpha subunit of a neuronal acetylcholine receptor expressed in both the peripheral and central nervous system. In this paper we report the isolation of a cDNA encoding the alpha subunit of a second acetylcholine receptor expressed in the central nervous system. Thus it is clear that there is a family of genes coding for proteins with sequence and structural homology to the alpha subunit of the muscle nicotinic acetylcholine receptor. Members of this gene family are expressed in different regions of the central nervous system and, presumably, code for subtypes of the nicotinic acetylcholine receptor.
1. The muscarinic depolarizing action of ACh on cortical neurones is associated with an increase in membrane resistance (mean Δ V /Δ R = 3·16 mV/MΩ).
2. ACh also promotes repetitive firing by slowing repolarization after spikes.
3. The depolarizing effect has a mean reversal level of −86·7 mV (with mean resting potential −56 mV).
4. It is concluded that as a muscarinic excitatory agent, ACh probably acts by reducing the resting K ⁺ conductance of cortical neurones, and also the delayed K ⁺ current of the action potential.
5. These results are discussed in relation to the possible role of ACh in cortical function.
Pyramidal cells in the CA1 field of guinea pig hippocampal slices were voltage-clamped using a single microelectrode, at 23-30 degrees C. Small inwardly relaxing currents triggered by step hyperpolarizations from holding potentials of -80 to -40 mV were investigated. Inward relaxations occurring for negative steps between -40 mV and -70 mV resembled M-currents of sympathetic ganglion cells: they were abolished by addition of carbachol, muscarine or bethanechol, as well as by 1 mM barium; the relaxations appeared to invert at around -80 mV; they became faster at more negative potentials; and the inversion potential was shifted positively by raising external K+ concentration. Inward relaxations triggered by steps negative to -80 mV, in contrast, appeared to reflect passage of another current species, which has been labelled IQ. Thus IQ did not invert negative to -80 mV, it was insensitive to muscarinic agonists or to barium, and it was blocked by 0.5-3 mM cesium (which does not block IM). Turn-on of IQ causes the well known droop in the hyperpolarizing electrotonic potential in these cells. The combined effects of IQ and IM make the steady-state current-voltage relation of CA1 cells slightly sigmoidal around rest potential. It is suggested that activation of cholinergic septal inputs to the hippocampus facilitates repetitive firing of pyramidal cells by turning off the M-conductance, without much change in the resting potential of the cell.
Membrane potential of lateral geniculate body relay neurons was monitored in chronic cats during the sleep-waking cycle. Neurons were tonically depolarized throughout paradoxical (P) sleep and the maximal level of polarization occurred during slow (S) sleep (mean difference of membrane potential between S and P sleep: + 10.2 +/- 1.3 mV, n = 6, range: 8-12 mV). Some features of the spontaneous activity of S and P sleep are briefly discussed in relation to the level of membrane potential. In particular it is suggested that the phasic depolarizations underlying the bursts of action potentials during S sleep, and which are reproduced retinal cell axons impinging upon the hyperpolarized membrane.
Cholinergic excitation of vertebrate neurones is frequently mediated through the action of acetylcholine on muscarinic (atropine-sensitve) receptors. This type of excitation differs substantially from the better known nicotinic excitation. One difference is that, instead of an increased membrane conductance, a decreased conductance (to K+ ions) frequently accompanies muscarinic depolarisation. This has been detected in sympathetic, cortical and hippocampal neurones. Using voltage-clamped frog sympathetic neurones we have now identified a distinctive voltage-sensitive K+-current, separate from the delayed rectifier current, as the prime target for muscarinic agonists. We have termed this current the M-current, IM.
Publisher Summary In recent years, the application of molecular biological techniques has established that there are at least five subtypes of muscarinic receptor, each with a unique pattern of distribution. Radio-ligand binding displacement studies of antagonist pharmacology of the individual receptors expressed in appropriate host cells have shown that each receptor does have a discrete antagonist profile, but that there are no single antagonists with sufficient selectivity to be clearly diagnostic for any particular receptor type. This has hampered the elucidation of the roles of muscarinic receptor subtypes, particularly, in cells which may simultaneously express more than one subtype, as is probably the case for neurones. The use of cell lines transfected with a gene encoding a single muscarinic receptor subtype has extended the characterization of muscarinic receptor subtypes beyond the pharmacology of the recognition site and has generated an additional classification on the basis of the downstream cellular mechanisms to which each subtype preferentially couples. This approach can clearly provide indications of likely coupling mechanisms of subtypes in, for example, the CNS neurones. Initial biochemical experiments with cell lines, such as the neuroblastoma x glioma hybrid NG108-15 have established two major groupings of muscarinic receptor subtypes, with ml, m3, and m5 receptors coupling preferentially to stimulation of phospholipase C (PLC) through a Pertussis toxin-insensitive G-protein, with subsequent elevation of IP3, while m2 and m4 receptors couple through a Pertussis toxin-sensitive G-protein to preferentially inhibit adenylyl cyclase.This chapter describes the electrophysiological consequences of muscarinic receptor activation using chemically differentiated NG108-15 cells transfected with ml-m4 receptor genes. These cells are especially useful for electrophysiological studies, because they express a range of K + and Ca 2+ channels similar to those found in many neuronal cell types. However, NGl08-15 cells do natively express the m4 muscarinic receptor.
Acetylcholine induces burst firing in nucleus reticularis neurons by activating a potassium conductance.
- McCormick
The molecular basis of muscarinic receptor diversity.
- Bonner
Two types of muscarinic response to acetylcholine in mammalian cortical neurons.
- McCormick
Anatomical and physiological basis of paradoxical sleep.
- Sakai