Abstract
Working memory impairment is a hallmark feature of schizophrenia and is thought be caused by dysfunctions in the prefrontal cortex (PFC) and associated brain regions. However, the neural circuit anomalies underlying this impairment are poorly understood. The aim of this study is to assess working memory performance in the chronic phencyclidine (PCP) mouse model of schizophrenia, and to identify the neural substrates of working memory. To address this issue, we conducted the following experiments for mice after withdrawal from chronic administration (14 days) of either saline or PCP (10 mg/kg): (1) a discrete paired-trial variable-delay task in T-maze to assess working memory, and (2) brain-wide c-Fos mapping to identify activated brain regions relevant to this task performance either 90 min or 0 min after the completion of the task, with each time point examined under working memory effort and basal conditions. Correct responses in the test phase of the task were significantly reduced across delays (5, 15, and 30 s) in chronic PCP-treated mice compared with chronic saline-treated controls, suggesting delay-independent impairments in working memory in the PCP group. In layer 2–3 of the prelimbic cortex, the number of working memory effort-elicited c-Fos+ cells was significantly higher in the chronic PCP group than in the chronic saline group. The main effect of working memory effort relative to basal conditions was to induce significantly increased c-Fos+ cells in the other layers of prelimbic cortex and the anterior cingulate and infralimbic cortex regardless of the different chronic regimens. Conversely, this working memory effort had a negative effect (fewer c-Fos+ cells) in the ventral hippocampus. These results shed light on some putative neural networks relevant to working memory impairments in mice chronically treated with PCP, and emphasize the importance of the layer 2–3 of the prelimbic cortex of the PFC.
Highlights
One of the critical unmet needs in schizophrenia management is an effective treatment for cognitive impairments [1, 2]
In the forced alternation training, there was no significant difference in latency to eat the pellet between mouse groups scheduled to undergo chronic saline or performance in the chronic phencyclidine (PCP) treatment, and both groups readily learned to run quickly through the maze to consume the food pellet (Fig 1C)
To address whether the working memory task differentially affects the activity patterns of dopamine neurons, we examined SNC and ventral tegmental area (VTA) c-Fos+ neurons using co-immunolabeling with TH, a marker of dopaminergic neurons in these regions (Fig 6A). c-Fos expression was comparable regardless of drug treatment, or working memory effort in the dorsal substantia nigra pars compacta (dSNC), medial SNC (mSNC), mVTA and interfascicular nucleus (IF), and slightly increased by working memory effort in the lVTA (p < 0.05) (S1 Table)
Summary
The aim of this study is to assess working memory performance in the chronic phencyclidine (PCP) mouse model of schizophrenia, and to identify the neural substrates of working memory. The primary aims of this study were to (1) evaluate the working memory performance in mice following chronic PCP administration and to (2) identify the neuronal circuitry relevant to task performance using c-Fos mapping
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