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Modulation of Hippocampal-Prefrontal Circuitry During Spatial Working Memory

Spellman, Timothy

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.

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More About This Work

Academic Units
Cellular Physiology and Biophysics
Thesis Advisors
Gordon, Joshua
Degree
Ph.D., Columbia University
Published Here
November 21, 2014
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