Aging-related alterations in orexin/hypocretin modulation of septo-hippocampal amino acid neurotransmission

The hippocampal formation is crucially involved the execution of learning and memory processes. Alterations in hippocampal function and anatomy are likely contributors to age-related cognitive dysfunction (Rosenzweig and Barnes, 2003). In human patients, normal aging is associated with significant volumetric reductions in the hippocampal formation (Du et al., 2001), and rodent studies indicate population specific neuronal loss in animal models of aging (Shetty and Turner, 1998, Vela et al., 2003, Stanley and Shetty, 2004, Gavilan et al., 2007, Stanley et al., 2011). While numerous studies have examined the effects of aging on intra-hippocampal function, alterations in extra-hippocampal input may also contribute to aging-induced hippocampal dysfunction. The septo-hippocampal pathway is comprised of cholinergic, GABAergic and glutamatergic projections from the medial septum of the basal forebrain to the hippocampus, (Frotscher and Leranth, 1985, Freund and Antal, 1988, Leranth and Frotscher, 1989, Sotty et al., 2003), and is instrumental to learning and memory as well as the maintenance of sleep-wake cycles (Lee et al., 1994, Bassant et al., 1995). Moreover, the medial septum is classically viewed as the hippocampal theta rhythm generator (Buzsaki, 2002). Theta activity is a 4–10 Hz rhythmic neuronal oscillation that occurs in the hippocampus during exploratory behavior and REM sleep, and is important for encoding of information by hippocampal place cells in learning and memory processes (Winson, 1978, Buzsaki, 2005). Appropriately, lesion of the medial septum or septo-hippocampal fibers results in impaired performance on hippocampally mediated tasks (Becker et al., 1980, Hagan et al., 1988, Numan and Quaranta, 1990) and reductions in hippocampal theta power (Green and Arduini, 1954, Yoder and Pang, 2005). Many of the effects observed following disruption of the septo-hippocampal transduction are similar to age-related alterations in cognitive and homeostatic processes. For instance, alongside decreased performance on cognitive tasks, aging is also associated with alterations in rhythmic sleep-wake cycles and reductions in hippocampal theta power (Lamour et al., 1989, Abe and Toyosawa, 1999). Sleep cycles in the elderly are characterized by an increase in fragmented daytime naps, earlier times of sleep onset, and alterations in the timing and frequency of nighttime rapid eye movement (REM) and slow wave sleep (Miles and Dement, 1980, Bliwise, 1993, Dijk et al., 1999) compared to young counterparts. Age-related alterations in homeostatic mechanisms, such as the disturbance in states of arousal and sleep are suggestive of hypothalamic dysfunction. Indeed, numerous studies have indicated a significant reduction in the pro-arousal peptide orexin (hypocretin) over the aging spectrum (Porkka-Heiskanen et al., 2004, Zhang et al., 2005, Brownell and Conti, 2010, Kessler et al., 2011). Orexin cell bodies are localized to the perifornical lateral hypothalamus yet influence a vast number of homeostatic and physiological behaviors, such as feeding, attention, arousal, addiction and cognition (de Lecea et al., 1998, Sakurai et al., 1998, Date et al., 1999, Jaeger et al., 2002, Telegdy and Adamik, 2002, Deadwyler et al., 2007, Aston-Jones et al., 2010, Sakurai et al., 2010), through widespread neuronal projections to regions that mediate these phenomena (Peyron et al., 1998, Date et al., 1999, Nambu et al., 1999). Both cholinergic and GABAergic cells of the medial septum receive a dense afferent input from hypothalamic orexin projections (Eggermann et al., 2001, Wu et al., 2002, Wu et al., 2004), and orexin modulation of these projection cells is speculated to modulate arousal and hippocampal theta rhythm (Espana et al., 2001, Gerashchenko et al., 2001). While direct orexin projections to the hippocampus are not as robust as those to medial septum, previous studies support a significant role for orexin in performance on tasks of hippocampal-dependent cognition (Akbari et al., 2006, Akbari et al., 2007, Akbari et al., 2008) and the induction of long term potentiation [LTP;(Selbach et al., 2004, Selbach et al., 2010, Akbari et al., 2011)]. Orexin may control hippocampal neurotransmission through direct as well as transsynaptic modulation of various pathways, including the septo-hippocampal pathway, and these effects are largely undefined. Furthermore, age-related alterations in the orexin system may contribute to hippocampal dysfunction via both direct and transsynaptic mechanisms. These studies were designed to examine the anatomical and neurochemical impact of aging on orexin modulation of hippocampal function, both directly, and by way of the medial septum, using immunohistochemistry and in vivo microdialysis. The hypothalamic neuropeptide orexin A (OxA) was infused into either CA1 or the medial septum while simultaneously measuring extracellular levels of hippocampal glutamate and GABA efflux in young and old rats. Moreover, orexin innervation of CA1 and the medial septum was assessed as a function of age in order to determine the impact of orexin modulation of hippocampal function over the course of normal aging.