Postnatal Phencyclidine-Induced Deficits in Decision Making Are Ameliorated by Optogenetic Inhibition of Ventromedial Orbitofrontal Cortical Glutamate Neurons
Michael M. Tranter, L. Faget, T. Hnasko, S. B. Powell, Daniel G Dillon, S. Barnes
Biological Psychiatry Global Open Science August 1, 2023 DOI: 10.1016/j.bpsgos.2023.08.002 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Sample size | 110 |
| Population | Male and female Wistar rats |
| Intervention | Phencyclidine (PCP) |
| Duration | PCP administered on postnatal days 7, 9, and 11; behavioral testing once daily for 20 days in adulthood |
| Measures | Probabilistic reversal learning task, Q-learning computational model of reinforcement learning |
| Key findings | Postnatal PCP treatment impaired probabilistic reversal learning in adult rats, and this deficit was reproduced in saline-treated rats by activating vmOFC glutamate neurons and reduced in PCP-treated rats by inhibiting them. The authors argue that PCP-induced decision-making deficits are associated with hyperactivity of vmOFC glutamate cells, suggesting that normalizing vmOFC activity may be a therapeutic target for schizophrenia-related cognitive impairment. |
Abstract
Background: The orbitofrontal cortex (OFC) is essential for decision making, and functional disruptions within the OFC are evident in schizophrenia. Postnatal phencyclidine (PCP) administration in rats is a neurodevelopmental manipulation that induces schizophrenia-relevant cognitive impairments. We aimed to determine whether manipulating OFC glutamate cell activity could ameliorate postnatal PCP-induced deficits in decision making.
Methods: Male and female Wistar rats (n = 110) were administered saline or PCP on postnatal days 7, 9, and 11. In adulthood, we expressed YFP (yellow fluorescent protein) (control), ChR2 (channelrhodopsin-2) (activation), or eNpHR 3.0 (enhanced halorhodopsin) (inhibition) in glutamate neurons within the ventromedial OFC (vmOFC). Rats were tested on the probabilistic reversal learning task once daily for 20 days while we manipulated the activity of vmOFC glutamate cells. Behavioral performance was analyzed using a Q-learning computational model of reinforcement learning.
Results: Compared with saline-treated rats expressing YFP, PCP-treated rats expressing YFP completed fewer reversals, made fewer win-stay responses, and had lower learning rates. We induced similar performance impairments in saline-treated rats by activating vmOFC glutamate cells (ChR2). Strikingly, PCP-induced performance deficits were ameliorated when the activity of vmOFC glutamate cells was inhibited (halorhodopsin).
Conclusions: Postnatal PCP-induced deficits in decision making are associated with hyperactivity of vmOFC glutamate cells. Thus, normalizing vmOFC activity may represent a potential therapeutic target for decision-making deficits in patients with schizophrenia.
Citations in the library
Cites 5
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