Topic: acetylcholine

Dopamine Acetylcholine interactions

Dopamine and Acetylcholine waves in the striatum

Targeting thalamic circuits rescues motor and mood deficits in PD mice

Although bradykinesia, tremor, and rigidity are hallmark motor defects in Parkinson’s disease (PD) patients, they also experience motor learning impairments and non-motor symptoms such as depression. The neural basis for these different PD symptoms are not well understood. While current treatments are effective for locomotion deficits in PD, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking. We found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN), and nucleus accumbens (NAc). While PF-->CPu and PF-->STN circuits are critical for locomotion and motor learning respectively, inhibition of the PF-->NAc circuit induced a depression-like state. While chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation at PF-->STN synapses restored motor learning behavior in PD model mice. Furthermore, activation of NAc-projecting PF neurons rescued depression-like PD phenotypes. Importantly, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.

New tools for monitoring and manipulating neural circuits

Dr. Looger will present updates on a variety of molecular tools for studying & manipulating neural circuits & other preparations. Topics include genetically encoded calcium indicators (including the new ultra-fast jGCaMP8 variants), neurotransmitter sensors (improved versions for following glutamate, GABA, acetylcholine, serotonin), optogenetic effectors including the new “enhanced Magnets” dimerizers, AAV serotypes for retrograde labeling & altered tropism, probes for correlative light-electron microscopy, chemical gene switches, etc. He will make all his slides freely available - so don’t worry about hurriedly taking notes; instead focus on questions and ideas for collaboration. Please bring your suggestions for molecular tools that would be transformative for the field.

Acetylcholine modulation of short-term plasticity is critical to reliable long-term plasticity in hippocampal synapses

CA3-CA1 synapses in the hippocampus are the initial locus of episodic memory. The action of acetylcholine alters cellular excitability, modifies neuronal networks, and triggers secondary signaling that directly affects long-term plasticity (LTP) (the cellular underpinning of memory). It is therefore considered a critical regulator of learning and memory in the brain. Its action via M4 metabotropic receptors in the presynaptic terminal of the CA3 neurons and M1 metabotropic receptors in the postsynaptic spines of CA1 neurons produce rich dynamics across multiple timescales. We developed a model to describe the activation of postsynaptic M1 receptors that leads to IP3 production from membrane PIP2 molecules. The binding of IP3 to IP3 receptors in the endoplasmic reticulum (ER) ultimately causes calcium release. This calcium release from the ER activates potassium channels like the calcium-activated SK channels and alters different aspects of synaptic signaling. In an independent signaling cascade, M1 receptors also directly suppress SK channels and the voltage-activated KCNQ2/3 channels, enhancing post-synaptic excitability. In the CA3 presynaptic terminal, we model the reduction of the voltage sensitivity of voltage-gated calcium channels (VGCCs) and the resulting suppression of neurotransmitter release by the action of the M4 receptors. Our results show that the reduced initial release probability because of acetylcholine alters short-term plasticity (STP) dynamics. We characterize the dichotomy of suppressing neurotransmitter release from CA3 neurons and the enhanced excitability of the postsynaptic CA1 spine. Mechanisms underlying STP operate over a few seconds, while those responsible for LTP last for hours, and both forms of plasticity have been linked with very distinct functions in the brain. We show that the concurrent suppression of neurotransmitter release and increased sensitivity conserves neurotransmitter vesicles and enhances the reliability in plasticity. Our work establishes a relationship between STP and LTP coordinated by neuromodulation with acetylcholine.

Cholinergic modulation of the cerebellum

Many studies have investigated the major glutamatergic inputs to the cerebellum, mossy fibres and climbing fibres, however far less is known about its neuromodulatory inputs. In particular, anatomical studies have described cholinergic input to the cerebellum, yet little is known about its role(s). In this talk, I will present our recent findings which demonstrate that manipulating acetylcholine receptors in the cerebellum causes effects at both a cellular and behavioural level. Activating acetylcholine receptors alters the intrinsic properties and synaptic inputs of cerebellar output neurons, and blocking these receptors results in deficits in a range of behavioural tasks.

Acetylcholine dynamics in the basolateral amygdala during reward learning

State-dependent cortical circuits

Spontaneous and sensory-evoked cortical activity is highly state-dependent, promoting the functional flexibility of cortical circuits underlying perception and cognition. Using neural recordings in combination with behavioral state monitoring, we find that arousal and motor activity have complementary roles in regulating local cortical operations, providing dynamic control of sensory encoding. These changes in encoding are linked to altered performance on perceptual tasks. Neuromodulators, such as acetylcholine, may regulate this state-dependent flexibility of cortical network function. We therefore recently developed an approach for dual mesoscopic imaging of acetylcholine release and neural activity across the entire cortical mantle in behaving mice. We find spatiotemporally heterogeneous patterns of cholinergic signaling across the cortex. Transitions between distinct behavioral states reorganize the structure of large-scale cortico-cortical networks and differentially regulate the relationship between cholinergic signals and neural activity. Together, our findings suggest dynamic state-dependent regulation of cortical network operations at the levels of both local and large-scale circuits. Zoom Meeting ID: 964 8138 3003 Contact host if you cannot connect.

State-dependent cortical circuits

Spontaneous and sensory-evoked cortical activity is highly state-dependent, promoting the functional flexibility of cortical circuits underlying perception and cognition. Using neural recordings in combination with behavioral state monitoring, we find that arousal and motor activity have complementary roles in regulating local cortical operations, providing dynamic control of sensory encoding. These changes in encoding are linked to altered performance on perceptual tasks. Neuromodulators, such as acetylcholine, may regulate this state-dependent flexibility of cortical network function. We therefore recently developed an approach for dual mesoscopic imaging of acetylcholine release and neural activity across the entire cortical mantle in behaving mice. We find spatiotemporally heterogeneous patterns of cholinergic signaling across the cortex. Transitions between distinct behavioral states reorganize the structure of large-scale cortico-cortical networks and differentially regulate the relationship between cholinergic signals and neural activity. Together, our findings suggest dynamic state-dependent regulation of cortical network operations at the levels of both local and large-scale circuits.

State-dependent regulation of cortical circuits

Spontaneous and sensory-evoked cortical activity is highly state-dependent, promoting the functional flexibility of cortical circuits underlying perception and cognition. Using neural recordings in combination with behavioral state monitoring, we find that arousal and motor activity have complementary roles in regulating local cortical operations, providing dynamic control of sensory encoding. These changes in encoding are linked to altered performance on perceptual tasks. Neuromodulators, such as acetylcholine, may regulate this state-dependent flexibility of cortical network function. We therefore recently developed an approach for dual mesoscopic imaging of acetylcholine release and neural activity across the entire cortical mantle in behaving mice. We find spatiotemporally heterogeneous patterns of cholinergic signaling across the cortex. Transitions between distinct behavioral states reorganize the structure of large-scale cortico-cortical networks and differentially regulate the relationship between cholinergic signals and neural activity. Together, our findings suggest dynamic state-dependent regulation of cortical network operations at the levels of both local and large-scale circuits.

Circuit mechanisms underlying the dynamic control of cortical processing by subcortical neuromodulators

Behavioral states such as arousal and attention can have profound effects on sensory processing, determining how – sometimes whether – a stimulus is processed. This state-dependence is believed to arise, at least in part, as a result of inputs to cortex from subcortical structures that release neuromodulators such as acetylcholine, noradrenaline, and serotonin, often non-synaptically. The mechanisms that underlie the interaction between these “wireless” non-synaptic signals and the “wired” cortical circuit are not well understood. Furthermore, neuromodulatory signaling is traditionally considered broad in its impact across cortex (within a species) and consistent in its form and function across species (at least in mammals). The work I will present approaches the challenge of understanding neuromodulatory action in the cortex from a number of angles: anatomy, physiology, pharmacology, and chemistry. The overarching goal of our effort is to elucidate the mechanisms behind local neuromodulation in the cortex of non-human primates, and to reveal differences in structure and function across cortical model systems.

The subcellular organization of excitation and inhibition underlying high-fidelity direction coding in the retina

Understanding how neural circuits in the brain compute information not only requires determining how individual inhibitory and excitatory elements of circuits are wired together, but also a detailed knowledge of their functional interactions. Recent advances in optogenetic techniques and mouse genetics now offer ways to specifically probe the functional properties of neural circuits with unprecedented specificity. Perhaps one of the most heavily interrogated circuits in the mouse brain is one in the retina that is involved in coding direction (reviewed by Mauss et al., 2017; Vaney et al., 2012). In this circuit, direction is encoded by specialized direction-selective (DS) ganglion cells (DSGCs), which respond robustly to objects moving in a ‘preferred’ direction but not in the opposite or ‘null’ direction (Barlow and Levick, 1965). We now know this computation relies on the coordination of three transmitter systems: glutamate, GABA and acetylcholine (ACh). In this talk, I will discuss the synaptic mechanisms that produce the spatiotemporal patterns of inhibition and excitation that are crucial for shaping directional selectivity. Special emphasis will be placed on the role of ACh, as it is unclear whether it is mediated by synaptic or non-synaptic mechanisms, which is in fact a central issue in the CNS. Barlow, H.B., and Levick, W.R. (1965). The mechanism of directionally selective units in rabbit's retina. J Physiol 178, 477-504. Mauss, A.S., Vlasits, A., Borst, A., and Feller, M. (2017). Visual Circuits for Direction Selectivity. Annu Rev Neurosci 40, 211-230. Vaney, D.I., Sivyer, B., and Taylor, W.R. (2012). Direction selectivity in the retina: symmetry and asymmetry in structure and function. Nat Rev Neurosci 13, 194-208

a5-containing nicotinic acetylcholine receptor regulation of fast GABAa-mediated inhibition during Up and Down states

Acetylcholine and Lateral Habenula partnership in shaping punishment anticipation

M1 acetylcholine receptor in somatostatin interneurons mediates cortical excitation/inhibition balance and antidepressant responses

Assessing the role of α7 nicotinic acetylcholine receptors in executive function using touchscreen technology in rat models

CHRFAM7A: A human specific α7- nicotinic acetylcholine receptor gene

Effects of acetylcholine receptor activation on properties of cerebellar nuclei neurons

Role of acetylcholine release in the prefrontal cortex during social interaction

Role of postsynaptic β2-containing nicotinic acetylcholine receptors in striatal circuits and related behavior

Upregulating acetylcholine enhances foraging optimality