Modulation of Hippocampal-Prefrontal Circuitry During Spatial Working Memory
Creators: Spellman, Timothy
Publisher: name: Columbia University
Year: 2015
Subjects: Psychophysiology

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.