What Is the Pathway Origin and Projections of Acetylcholine?
In the autonomic nervous system, acetylcholine (ACh) is the neurotransmitter in the preganglionic sympathetic and parasympathetic neuron. ACh is also the neurotransmitter at the adrenal medulla and serves as the neurotransmitter at all the parasympathetic innervated organs. ACh is also the neurotransmitter at the sweat glands, and at the piloerector muscle of the sympathetic ANS. In the central nervous system, ACh is found primarily in interneurons, as orange and green cell clusters. A few important long-axon cholinergic pathways have also been identified. Noteworthy is the cholinergic projection from the nucleus basalis of Meynert (in the basal forebrain) to the forebrain neocortex and associated limbic structures.
Methamphetamine (MA) increases dopamine (DA) levels within the mesolimbic pathway and acetylcholine (ACh), a neurotransmitter known to increase DA cell firing and release and mediate reinforcement, within the ventral tegmental area (VTA). The laterodorsal tegmental (LDT) and pedunculopontine tegmental (PPT) nuclei provide cholinergic input to the VTA; however, the contribution of LDT- and PPT-derived ACh to MA-induced DA and ACh levels and locomotor activation remains unknown. The first experiment examined the role of LDT-derived ACh in MA locomotor activation by reversibly inhibiting these neurons with bilateral intra-LDT microinjections of the M2 receptor agonist oxotremorine (OXO). Male C57BL/6 J mice were given a bilateral 0.1 µl OXO (0, 1, or 10 nM/side) microinjection immediately prior to IP saline or MA (2 mg/kg). The highest OXO concentration significantly inhibited both saline-and MA-primed locomotor activity. In a second set of experiments we characterized the individual contributions of ACh originating in the LDT or pedunculopontine tegmental nucleus (PPT) to MA-induced levels of ACh and DA by administering intra-LDT or PPT OXO and performing in vivo microdialysis in the VTA and NAc. Intra-LDT OXO dose-dependently attenuated the MA-induced increase in ACh within the VTA but had no effect on DA in NAc. Intra-PPT OXO had no effect on ACh or DA levels within the VTA or NAc, respectively. In order to test this, we reversibly inhibited cholinergic neurons in the LDT or PPT via a bilateral microinjection of the muscarinic ACh receptor agonist oxotremorine sesquifumarate (OXO). OXO preferentially binds to M2-type ACh receptors, which are inhibitory autoreceptors that activate a TTX-insensitive hyperpolarization thereby inhibiting neuronal activity and terminal ACh release.
Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity, and coordinates firing of groups of neurons. As a result, it changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here, we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss consequences of this signaling on behaviors related to drug abuse, attention, food intake, and affect. The diverse effects of acetylcholine depend on site of release, receptor subtypes, and target neuronal population; however, a common theme is that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action. The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors. The definition of a neuromodulator is flexible, but has evolved to describe any kind of neurotransmission that is not directly excitatory (mediated through ionotropic glutamate receptors) or inhibitory (mediated through ionotropic gamma-aminobutyric acid [GABA] receptors) (Ito and Schuman, 2008; Siggins, 1979). Neuromodulation can be thought of as a change in the state of a neuron or group of neurons that alters its response to subsequent stimulation. A number of models have been proposed to explain the actions of ACh in the central nervous system (CNS). For example, ACh has been suggested to be critical for the response to uncertainty, such that an increase in cholinergic tone predicts the unreliability of predictive cues in a known context and improves the signal-to-noise ratio in a learning environment (Yu and Dayan, 2005).
Ultimately, in vivo calcium imaging of DA and ACh terminals arising from functionally defined cell populations, in different projection sites, within varied behavioral contexts would provide better resolved information about the contribution of these two neuromodulators to naturalistic actions. In a similar way, site and function specific targeting of axons in a loss of function experimental design would complement the previous information and provide causal evidence of BG control of actions. Once this information is available, it would be possible to design medical approaches that can treat highly specific aspects of neurodegenerative disorders leaving all other functions intact. For example, different strategies could be taken to treat the motor symptoms of PD without carrying a cognitive decline and vice versa.
H.T. Ito, E.M. Schuman Frequency-dependent signal transmission and modulation by neuromodulators Front. Neurosci., 2 (2008), pp. 138-144
G.R. Siggins Neurotransmitters and neuromodulators and their mediation by cyclic nucleotides Adv. Exp. Med. Biol., 116 (1979), pp. 41-64
J.F. Smiley, F. Morrell, M.M. Mesulam, Cholinergic synapses in human cerebral cortex: an ultrastructural study in serial sections, Exp. Neurol., 144 (1997), pp. 361-368
N. Takata, T. Mishima, C. Hisatsune, T. Nagai, E. Ebisui, K. Mikoshiba, H. Hirase, Astrocyte calcium signaling transforms cholinergic modulation to cortical plasticity in vivo, J. Neurosci., 31 (2011