Effects of acetylcholine on neuronal properties, spatial novelty and behavioral uncertainty
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Abstract
The role of acetylcholine in the hippocampal formation can be observed across multiple scales and cognitive states. Acetylcholine alters neuronal excitability and synaptic plasticity and has been linked to specific aspects of memory encoding and in modulating theta rhythmicity in the hippocampal formation. Acetylcholine has been linked to the neural mechanisms for response to novelty and uncertainty as well as arousal and attention. This thesis explores the effects of acetylcholine across different scales. Firstly, I tested potential local circuit mechanisms that could modulate encoding and attention and the response to novelty. I recorded from genetically identified parvalbumin (PV+), and somatostatin (SST+) interneurons in medial entorhinal cortex (MEC) in acute mouse brain slices before and during pharmacological activation of cholinergic receptors with the cholinergic agonist carbachol to assess potential changes in excitability of these inhibitory interneurons. We find that PV+ interneurons in layer II/III MEC exhibit both hyperpolarizing and depolarizing muscarinic responses to cholinergic activation and that somatostatin positive interneurons are predominantly depolarized by cholinergic activation. Both interneuron classes display complex increases in spectral power during cholinergic activation, which are reflected by an increase in variability in the baseline membrane potential in voltage traces. These effects could shift the dynamics of local circuits toward attention and encoding. Secondly, I use an environmental novelty task to investigate dynamic changes in medial septal cholinergic neuron calcium activity at the onset of novel environment exposure and during animal exploration. Fiber photometry recordings of the medial septum show that GCAMP6f activity of cholinergic neurons increases at the onset of field exposure, an effect which decreases over days. Presentation of a novel open field following habituation leads to an increase in cholinergic activity. These changes in acetylcholine levels with novelty could modulate circuit dynamics to enhance mechanisms for encoding or attention. Finally, I present fibre photometry data recording of GCAMP6f cholinergic neuron activity in the medial septum of mice performing in a virtual reality environment in an expected uncertainty task, which was motivated by theories about the relative influence of expected versus unexpected uncertainty on modulatory regulation. These studies demonstrate components of the potential role of acetylcholine in regulating the dynamics of local cortical circuits in the hippocampus and entorhinal cortex for encoding or attention to environmental stimuli important for memory-guided behavior.
Description
2024