Title: Modulation of Hippocampal-Prefrontal Circuitry During Spatial Working Memory
Description: Spatial working memory (SWM) is an essential feature of goal-directed action. Locating a resource, a threat, or even oneself within a dynamic or unfamiliar environment requires a cached representation of relevant spatial features that must be continuously updated, preserved, and applied as needed to the execution of appropriate behaviors (Baddeley and Hitch 1974). SWM is disrupted in schizophrenia, as well as in multiple animal models of the disease. Patients with schizophrenia show impairment on tasks with both verbal and spatial working memory demands (Park and Holzman 1992, Conklin, Curtis et al. 2000) and exhibit abnormalities in neurophysiological signals that are associated with normal cognitive performance. More specifically, convergent data from diverse studies suggests that disruption of long-range functional connectivity may underlie diverse cognitive and physiological symptoms of the schizophrenia. It is therefore imperative that pathways of long-range functional connectivity that support the cognitive processes impaired in schizophrenia be identified and characterized, so that effective interventions can be targeted to the appropriate neural structures and pathways.

Despite long-standing interest in the neurobiological underpinnings of working memory, its multiple cognitive components, distributed anatomical constituents, and distinct temporal phases have rendered its investigation elusive (Logie 1995, Miyake and Shah 1999, Andrade 2001, de Zubicaray, McMahon et al. 2001, Baddeley 2003, Klauer and Zhao 2004). Despite these challenges, an extensive body of work supports the idea that the prefrontal cortex (PFC) plays a central role in the successful execution of tasks requiring spatial working memory (Curtis and D'Esposito 2004). Moreover, the joint contribution of medial prefrontal cortex (mPFC) and hippocampus (HPC) supports successful spatial working memory in rodents (Lee and Kesner 2003, Jones and Wilson 2005, Wang and Cai 2006, Hyman, Zilli et al. 2010, Sigurdsson, Stark et al. 2010). It remains unclear, however, which phase(s) of SWM (encoding, maintenance, and/or retrieval) require the joint participation of HPC and mPFC, what behaviorally relevant information is conveyed between the two structures, and by what anatomical pathway(s) they interact.

Although HPC and mPFC share multiple second-degree anatomical connections, including via striatum, amygdala, entorhinal cortex, and midline thalamic nuclei, direct connectivity between the two structures is confined to a unidirectional projection from the Ca1/subiculum of the ventral hippocampus (vHPC) to prelimbic (PL) and infralimbic (IL) regions of the mPFC (Jay and Witter 1991, Hoover and Vertes 2007, Oh 2014). Cells of both vHPC and mPFC exhibit location-specific firing that could function to encode spatial cues critical to SWM (Jung, Wiener et al. 1994, Poucet, Thinus-Blanc et al. 1994, Jung, Qin et al. 1998, Hok, Save et al. 2005, Kjelstrup, Solstad et al. 2008, Burton, Hok et al. 2009, Royer, Sirota et al. 2010, Keinath, Wang et al. 2014). Moreover, damage to the vHPC disrupts representations of salient locations in mPFC (Burton, Hok et al. 2009), suggesting that the vHPCmPFC projection may transmit SWM critical location information. We therefore tested the role of vHPC-mPFC afferents in spatial working memory using an a projection silencing approach that afforded anatomical and temporal precision and found that the vHPC-mPFC direct input is necessary for encoding, not maintenance or retrieval, of SWM-dependent cues.

Combining this approach with in vivo extracellular recordings of mPFC single units, we found that location-selective firing in the mPFC during SWM is dependent on vHPC direct input exclusively during the encoding phase of each trial. Finally, we found evidence that the transmission of task-critical information in the vHPC-mPFC pathway is mediated by the synchronizing of mPFC cells to gamma oscillations in the vHPC. Together, these findings suggest a role for the vHPC-mPFC pathway in the encoding of cues critical to SWM and may indicate a potential locus of pathophysiological disruption underlying the cognitive impairments associated with schiziphrenia.