Coordinated Acetylcholine Release in Prefrontal Cortex and Hippocampus Is Associated with Arousal and Reward on Distinct Timescales.

Cholinergic neurotransmission throughout the neocortex and hippocampus regulates arousal, learning, and attention. However, owing to the poorly characterized timing and location of acetylcholine release, its detailed behavioral functions remain unclear. Using electrochemical biosensors chronically implanted in mice, we made continuous measurements of the spatiotemporal dynamics of acetylcholine release across multiple behavioral states. We found that tonic levels of acetylcholine release were coordinated between the prefrontal cortex and hippocampus and maximal during training on a rewarded working memory task. Tonic release also increased during REM sleep but was contingent on subsequent wakefulness. In contrast, coordinated phasic acetylcholine release occurred only during the memory task and was strongly localized to reward delivery areas without being contingent on trial outcome. These results show that coordinated acetylcholine release between the prefrontal cortex and hippocampus is associated with reward and arousal on distinct timescales, providing dual mechanisms to support learned behavior acquisition during cognitive task performance.

Cholinergic modulation of hippocampal network function.

Cholinergic septohippocampal projections from the medial septal area to the hippocampus are proposed to have important roles in cognition by modulating properties of the hippocampal network. However, the precise spatial and temporal profile of acetylcholine release in the hippocampus remains unclear making it difficult to define specific roles for cholinergic transmission in hippocampal dependent behaviors. This is partly due to a lack of tools enabling specific intervention in, and recording of, cholinergic transmission. Here, we review the organization of septohippocampal cholinergic projections and hippocampal acetylcholine receptors as well as the role of cholinergic transmission in modulating cellular excitability, synaptic plasticity, and rhythmic network oscillations. We point to a number of open questions that remain unanswered and discuss the potential for recently developed techniques to provide a radical reappraisal of the function of cholinergic inputs to the hippocampus.

Long-term depression of synaptic kainate receptors reduces excitability by relieving inhibition of the slow afterhyperpolarization.

Kainate receptors (KARs) are ionotropic glutamate receptors that also activate noncanonical G-protein-coupled signaling pathways to depress the slow afterhyperpolarization (sAHP). Here we show that long-term depression of KAR-mediated synaptic transmission (KAR LTD) at rat hippocampal mossy fiber synapses relieves inhibition of the sAHP by synaptic transmission. KAR LTD is induced by high-frequency mossy fiber stimulation and natural spike patterns and requires activation of adenosine A2A receptors. Natural spike patterns also cause long-term potentiation of NMDA receptor-mediated synaptic transmission that overrides the effects of KAR LTD on the cellular response to low-frequency synaptic input. However, KAR LTD is dominant at higher frequency synaptic stimulation where it decreases the cellular response by relieving inhibition of the sAHP. Thus we describe a form of glutamate receptor plasticity induced by natural spike patterns whose primary physiological function is to regulate cellular excitability.

Increased axonal bouton dynamics in the aging mouse cortex.

Aging is a major risk factor for many neurological diseases and is associated with mild cognitive decline. Previous studies suggest that aging is accompanied by reduced synapse number and synaptic plasticity in specific brain regions. However, most studies, to date, used either postmortem or ex vivo preparations and lacked key in vivo evidence. Thus, whether neuronal arbors and synaptic structures remain dynamic in the intact aged brain and whether specific synaptic deficits arise during aging remains unknown. Here we used in vivo two-photon imaging and a unique analysis method to rigorously measure and track the size and location of axonal boutons in aged mice. Unexpectedly, the aged cortex shows circuit-specific increased rates of axonal bouton formation, elimination, and destabilization. Compared with the young adult brain, large (i.e., strong) boutons show 10-fold higher rates of destabilization and 20-fold higher turnover in the aged cortex. Size fluctuations of persistent boutons, believed to encode long-term memories, also are larger in the aged brain, whereas bouton size and density are not affected. Our data uncover a striking and unexpected increase in axonal bouton dynamics in the aged cortex. The increased turnover and destabilization rates of large boutons indicate that learning and memory deficits in the aged brain arise not through an inability to form new synapses but rather through decreased synaptic tenacity. Overall our study suggests that increased synaptic structural dynamics in specific cortical circuits may be a mechanism for age-related cognitive decline.