Transient Inactivation of the Neonatal Ventral Hippocampus Permanently Disrupts the Mesolimbic Regulation of Prefrontal Cholinergic Transmission: Implications for Schizophrenia

Abstract

These experiments determined the mesolimbic modulation of cortical cholinergic transmission in a neurodevelopmental model of schizophrenia. Mesolimbic-cholinergic abnormalities are hypothesized to contribute to the cognitive deficits seen in schizophrenia. Stimulation of NMDA receptors in nucleus accumbens (NAC) increases acetylcholine (ACh) release in the prefrontal cortex (PFC), a mechanism recently demonstrated to contribute to the control of attentional performance. We determined the ability of intra-NAC administration of NMDA to increase prefrontal ACh levels in adult rats that had received bilateral infusions of tetrodotoxin (TTX) to transiently interrupt impulse flow in the ventral hippocampus (VH) during development. Rats received infusions of TTX or saline on postnatal day 7 (PD7) or day 32 (PD32), and the effects of NAC NMDA receptor stimulation on prefrontal cholinergic neurotransmission were assessed in adulthood. In animals treated as controls on PD7, NMDA increased prefrontal ACh levels by 121% above baseline. In contrast, PD7 infusions of TTX into the VH abolished the ability of NAC NMDA to activate prefrontal cholinergic neurotransmission (7% increase). In animals that received TTX infusions on PD32, NMDA-evoked cholinergic activity did not differ from controls, indicating a restricted, neonatal critical period during which VH TTX impacts the organization of mesolimbic-basal forebrain-cortical circuitry. Importantly, the failure of NAC NMDA to evoke cholinergic activity in rats treated with TTX on PD7 did not reflect a reduced excitability of corticopetal cholinergic neurons because administration of amphetamine produced similar elevations of prefrontal ACh levels in PD7 TTX and PD7 control animals. A third series of experiments demonstrated that the effects of PD7 TTX are a specific consequence of transient disruption of impulse flow in the VH. Intra-NAC NMDA evoked prefrontal ACh release in rats receiving TTX, on PD7, into the dorsal hippocampus (DH), basolateral amygdala, or NAC. Thus, impulse flow specifically within the VH, during a sensitive period of development, is necessary for the functional organization of a mesolimbic-cortical circuit known to mediate attentional control processes. Therefore, neonatal inactivation of VH represents an effective animal model for studying the basis of certain cognitive symptoms of schizophrenia.

Dorsal and Ventral Hippocampus Differentiate in Functional Pathways and Differentially Associate with Neurological Disease-Related Genes during Postnatal Development

“…Functional differentiation between the dorsal and ventral regions of the hippocampus has been experimentally and bioinformatically demonstrated in previous studies, strongly suggesting that hippocampal regions may have differential roles in distinct diseases. Indeed, schizophrenia, anxiety and depression have been associated with altered function of the ventral hippocampus (Tseng et al, 2009 ; Fanselow and Dong, 2010 ; Brooks et al, 2011 ; Small et al, 2011 ; O’Reilly et al, 2015 ).…”

Early developmental elevations of brain kynurenic acid impair cognitive flexibility in adults: Reversal with galantamine

“…The timing of kynurenine treatment used here was designed to span a rather broad pre- and postnatal period, comprising developmental stages where perturbations are known to significantly affect cognitive functions in adults (Peterschmitt et al, 2007; Marquis et al, 2008; Alexander et al, 2009; Brady et al, 2010; Brooks et al, 2011; Pocivavsek et al, 2012). In follow-up studies based on the present results, we are currently evaluating whether exposure to kynurenine, and hence elevation of brain KYNA levels, during more restricted periods of early development, or extended treatments during adulthood, would have similarly enduring, adverse effects on cognitive processes.…”

Early Prefrontal Functional Blockade in Rats Results in Schizophrenia-Related Anomalies in Behavior and Dopamine

“…The microinjection site in the PFC was identified by postmortem using Evans blue (Sigma), a vital dye added to the solutions of PBS and TTX, and reported as remaining visible in the cerebral tissue several weeks after injection (Martin and Ghez, 1999;Peterschmitt et al, 2007;Meyer et al, 2009;Brooks et al, 2011;Meyer and Louilot, 2011). Each rat pup was identified by means of small three-digit ear tags , Harvard Apparatus, Les Ulis, France).…”