Deciphering the Functions of Raphe-Hippocampal Serotonergic and Glutamatergic Circuits and Their Deficits in Alzheimer's Disease.

Subcortical innervation of the hippocampus by the raphe nucleus is essential for emotional and cognitive control. The two major afferents from raphe to hippocampus originate from serotonergic and glutamatergic neurons, of which the serotonergic control of hippocampal inhibitory network, theta activity, and synaptic plasticity have been extensively explored in the growing body of literature, whereas those of glutamatergic circuits have received little attention. Notably, both serotonergic and glutamatergic circuits between raphe and hippocampus are disrupted in Alzheimer's disease (AD), which may contribute to initiation and progression of behavioral and psychological symptoms of dementia. Thus, deciphering the mechanism underlying abnormal raphe-hippocampal circuits in AD is crucial to prevent dementia-associated emotional and cognitive symptoms. In this review, we summarize the anatomical, neurochemical, and electrophysiological diversity of raphe nuclei as well as the architecture of raphe-hippocampal circuitry. We then elucidate subcortical control of hippocampal activity by raphe nuclei and their role in regulation of emotion and cognition. Additionally, we present an overview of disrupted raphe-hippocampal circuits in AD pathogenesis and analyze the available therapies that can potentially be used clinically to alleviate the neuropsychiatric symptoms and cognitive decline in AD course.