ReviewRegulation of cortical acetylcholine release: Insights from in vivo microdialysis studies
Introduction
It has now been roughly a century since the identification of acetylcholine (ACh) as a neurotransmitter in the mammalian central nervous system, and some six decades since Richter and Crossland published their findings on the relationship between physiological state and brain ACh content [126]. With the advent of the cortical cup and push–pull cannula techniques in the 1960s and 1970s, investigators were able to go beyond post-mortem measurement of ACh content and directly measure levels of this neurotransmitter in the living brain. It was the introduction of modern in vivo microdialysis and its widespread application beginning in the 1980s, however, which revolutionized our understanding of the physiological, pharmacological and behavioral mechanisms underlying ACh release. For example, early studies on the relationship between anesthesia and brain ACh content generally large increases peaking when the animal was sacrificed 30–60 min post-anesthesia (e.g. [40]). The first microdialysis studies using the same or similar anesthetics showed virtually the opposite effect—i.e. anesthetics produce a rapid decrease in brain ACh efflux (e.g. [75]). While the original studies may have correctly interpreted their results—that anesthesia increased post-mortem brain ACh content by inhibiting its ‘liberation’, in vivo microdialysis was important in eliminating a significant intervening level of inference between ACh measurement and the phenomenon of interest—the effect of a manipulation on ACh release. The improved temporal and spatial resolution of microdialysis over its predecessors, and its ready applicability to awake, behaving animal models converged with clinical literature on the postulated role of the cholinergic system in several neurodegenerative and neuropsychiatric conditions. This combination of factors led to a rapid increase in studies using microdialysis to study ACh release in the mammalian brain (Fig. 1).
Thus, ACh release has been measured using a variety of techniques in numerous parts of the central nervous system, with the functional significance of that dependent variable inferred on the basis of the anatomical source of ACh, the brain region where it is being measured, and the pharmacological or behavioral independent variable employed to invoke (or inhibit) release. The reader is referred elsewhere for a more exhaustive overview of all of these factors [121], which is far beyond the scope of this review. Rather, this paper will focus primarily on studies of ACh release in the mammalian cerebral cortex. Furthermore, because much of what we know about the nature of cortical ACh release has derived from in vivo microdialysis studies over the past two decades, this will form the basis for much of this review. Finally, we will conclude with a brief discussion of some current issues in the field of cortical ACh release and how they may be resolved by the next generation of tools for the measurement of cortical ACh release.
Section snippets
Microdialysis measurement of ACh: release versus efflux
ACh release represents the presynaptic component of endogenous cholinergic neurotransmission in the brain. ACh release follows a series of presynaptic electrical and signaling cascades (including sodium channel-dependent depolarization and calcium-dependent vesicular docking) culminating in the quantal elevation of synaptic ACh concentrations. Efflux, as measured extrasynaptically by in vivo microdialysis is a dependent measure reflecting a summed correlate of release, degradation and
Regulation of cortical ACh release by basal forebrain afferents: linking function with anatomy
Mammalian forebrain cholinergic neurons have been broadly grouped into four clusters, using the nomenclature of Mesulam et al. [94]: the first three subgroups (Ch1-3) consist of neurons in the medial septum and vertical and horizontal limbs of the diagonal band of Broca, and provide cholinergic innervation of the hippocampus and olfactory bulb. While some reports in rodents suggest that a portion of cholinergic innervation of the medial prefrontal cortex additionally arises from the diagonal
Cortical ACh release in neuropsychiatric disorders
Given the involvement of cortical cholinergic neurotransmission in arousal and attention, a potential role of altered ACh release has been hypothesized for a number of neuropsychiatric conditions characterized, at least in part, by cognitive dysfunction. Cortical ACh release in some of these disorders derives from a strong empirical and conceptual basis, stemming from human clinical literature as well as a robust animal literature demonstrating that cortical ACh release is increased in a manner
Basal cortical ACh release: what is it, what drives it and what does it mean?
‘Basal’ cortical ACh efflux is a physiological phenomenon that can be defined as the cortical ACh release measured by the microdialysis technique in the absence of any systematic behavioral or pharmacological manipulation. The term basal implies nothing regarding the behavioral status of the animal, only the lack of a controlled independent variable. In the non-anesthetized preparation, then, basal efflux may be measured in an animal which is asleep or awake, moving or motionless, or any
Conclusions
Measurement of ACh release represents the most direct indicator of the presynaptic component of cholinergic transmission in the cerebral cortex. In vivo microdialysis studies over the past three decades have allowed for the emergence of a tremendous amount of new information regarding the pharmacological regulation of ACh release, the role of the corticopetal cholinergic system in normal behavioral and cognitive processes, and the pathological correlates of dysregulated cholinergic transmission
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2020, Neurobiology of StressCitation Excerpt :When the N = 11 CS+ rats (including rats with placement outside the BLA) were divided into ER and EC phenotypes based on freezing during extinction learning with microdialysis, only two of seven rats in the CS+ group with probe placement in the BLA showed the ER phenotype (N = 5 EC); two subjects in one of these groups was not sufficiently powered to conduct reliable statistical analysis on any endpoints. This ER/EC comparison was also confounded by using an ACHE inhibitor in the perfusate to allow reliable detection of ACH release during microdialysis, which may have also modified freezing during the extinction learning trial and therefore the extinction phenotype of the animal (Fadel, 2011; Konig et al., 2018). Given that many forms of stress increase glutamate release in the amygdala (see (Reznikov et al., 2007; Wilson et al., 2015)), and the anatomical evidence suggesting that acetylcholine and glutamate might be co-released (Nickerson Poulin et al., 2006), it was somewhat surprising that we found no differences in glutamate efflux even in the CS + group.
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2013, NeuroImageCitation Excerpt :The nucleus basalis of Meynert (NBM) provides the principal cholinergic innervation of the cortex. The specific regional density of cholinergic innervation from NBM has not been reported in detail, however the existence of reciprocal cortical excitatory inputs to NBM coming from a few specific areas including insula and prefrontal regions is well known (Fadel, 2011). In addition the pedunculopontine tegmental nucleus (PPT) and the laterodorsal tegmental nucleus (LDT) provide the main cholinergic innervation of the thalamus, and contribute to a minor portion of cholinergic input to cortical regions including the cingulate cortex (Mesulam, 1995).
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2013, Biochemical PharmacologyCitation Excerpt :The endogenous ACh values detected in this study do not correspond to the assumed ACh concentration [41], but we believe this discrepancy may be explained by the inherent limitations of the microdialysis technique compared to enzyme-coated microelectrodes. The latter samples directly from the extracellular space with high temporal resolution, whereas the spatial and temporal resolution of microdialysis is compromised by the dependence on diffusion of analytes through a semipermeable membrane over minutes, thus representing both analyte release, degradation and diffusion, as well as by the occurrence of gliosis and edema [41,51]. The fact that NS9283 evoked robust glutamate release in mPFC strongly indicate expression of (α4)3(β2)2 nAChRs in this region, and this finding is supported by the observed activity of NS9283 at native rat nicotinic receptors in thalamocortical neurons ex vivo [35].