Xanomeline restores endogenous nicotinic acetylcholine receptor signaling in mouse prefrontal cortex.

Cholinergic synapses in prefrontal cortex are vital for attention, but this modulatory system undergoes substantial pre- and post-synaptic alterations during adulthood. To examine the integrated impact of these changes, we optophysiologically probe cholinergic synapses ex vivo, revealing a clear decline in neurotransmission in middle adulthood. Pharmacological dissection of synaptic components reveals a selective reduction in postsynaptic nicotinic receptor currents. Other components of cholinergic synapses appear stable, by contrast, including acetylcholine autoinhibition, metabolism, and excitation of postsynaptic muscarinic receptors. Pursuing strategies to strengthen cholinergic neurotransmission, we find that positive allosteric modulation of nicotinic receptors with NS9283 is effective in young adults but wanes with age. To boost nicotinic receptor availability, we harness the second messenger pathways of the preserved excitatory muscarinic receptors with xanomeline. This muscarinic agonist and cognitive-enhancer restores nicotinic signaling in older mice significantly, in a muscarinic- and PKC-dependent manner. The rescued nicotinic component regains youthful sensitivity to allosteric enhancement: treatment with xanomeline and NS9283 restores cholinergic synapses in older mice to the strength, speed, and receptor mechanism of young adults. Our results reveal a new and efficient strategy to rescue age-related nicotinic signaling deficits, demonstrating a novel pathway for xanomeline to restore cognitively-essential endogenous cholinergic neurotransmission.

Endogenous Acetylcholine and Its Modulation of Cortical Microcircuits to Enhance Cognition.

Acetylcholine regulates the cerebral cortex to sharpen sensory perception and enhance attentional focus. The cellular and circuit mechanisms of this cholinergic modulation are under active investigation in sensory and prefrontal cortex, but the universality of these mechanisms across the cerebral cortex is not clear. Anatomical maps suggest that the sensory and prefrontal cortices receive distinct cholinergic projections and have subtle differences in the expression of cholinergic receptors and the metabolic enzyme acetylcholinesterase. First, we briefly review this anatomical literature and the recent progress in the field. Next, we discuss in detail the electrophysiological effects of cholinergic receptor subtypes and the cell and circuit consequences of their stimulation by endogenous acetylcholine as established by recent optogenetic work. Finally, we explore the behavioral ramifications of in vivo manipulations of endogenous acetylcholine. We find broader similarities than we expected between the cholinergic regulation of sensory and prefrontal cortex, but there are some differences and some gaps in knowledge. In visual, auditory, and somatosensory cortex, the cell and circuit mechanisms of cholinergic sharpening of sensory perception have been probed in vivo with calcium imaging and optogenetic experiments to simultaneously test mechanism and measure the consequences of manipulation. By contrast, ascertaining the links between attentional performance and cholinergic modulation of specific prefrontal microcircuits is more complicated due to the nature of the required tasks. However, ex vivo optogenetic manipulations point to differences in the cholinergic modulation of sensory and prefrontal cortex. Understanding how and where acetylcholine acts within the cerebral cortex to shape cognition is essential to pinpoint novel treatment targets for the perceptual and attention deficits found in multiple psychiatric and neurological disorders.

Chronic social isolation exerts opposing sex-specific consequences on serotonin neuronal excitability and behaviour.

Social isolation raises the risk for mood disorders associated with serotonergic disruption. Yet, the underlying mechanisms by which the stress of social isolation increases risk are not well understood. Men and women are differently vulnerable; however, this modulating role of sex is challenging to study in humans under carefully controlled conditions. Therefore, we investigated this question in mice of both sexes, asking how the long-term stress of social isolation (from weaning into adulthood) affects the excitability of serotonin neurons in the dorsal raphe nucleus as well as mouse behaviour. The electrophysiological experiments and the first set of behavioural tests were conducted in young adult mice, with additional behavioural assays completed as the mice matured to assess the stability of their behavioural phenotype. We found that social isolation exerted seemingly-opposite effects in male and female mice, relative to their respective group-housed littermate controls. This distinctive pattern was observed for the effect of social isolation on the control of serotonergic neuron excitability via the SK family of calcium-activated potassium channels. Furthermore, we observed a similar and consistent pattern on tests relevant to assessing the efficacy of anti-depressant medicines, including the forced swim test, the novelty-suppressed feeding test, and the sucrose preference test. These findings underscore the concept that stress-elicited illness manifests distinctly in males and females and that treatments aimed at restoring serotonergic function may require a sex-specific approach. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Mapping the physiological and molecular markers of stress and SSRI antidepressant treatment in S100a10 corticostriatal neurons.

In mood disorders, psychomotor and sensory abnormalities are prevalent, disabling, and intertwined with emotional and cognitive symptoms. Corticostriatal neurons in motor and somatosensory cortex are implicated in these symptoms, yet mechanisms of their vulnerability are unknown. Here, we demonstrate that S100a10 corticostriatal neurons exhibit distinct serotonin responses and have increased excitability, compared with S100a10-negative neurons. We reveal that prolonged social isolation disrupts the specific serotonin response which gets restored by chronic antidepressant treatment. We identify cell-type-specific transcriptional signatures in S100a10 neurons that contribute to serotonin responses and strongly associate with psychomotor and somatosensory function. Our studies provide a strong framework to understand the pathogenesis and create new avenues for the treatment of mood disorders.