Altered Prefrontal Cortical Metabolic Response to Mesocortical Activation in Adult Animals with a Neonatal Ventral Hippocampal Lesion

Abstract

Background-Adult animals with a neonatal ventral hippocampal lesion (NVHL) exhibit deficits in working memory and sensorimotor gating similar to those observed in schizophrenia. As cognitive deficits in this disorder are typically associated with changes in cortical metabolic levels, we investigated here whether an NVHL affects metabolic responses to ventral tegmental area (VTA) activation, a procedure that elicits abnormal cell firing in the prefrontal cortex (PFC) of NVHL animals.

Post-Pubertal Disruption of Medial Prefrontal Cortical Dopamine–Glutamate Interactions in a Developmental Animal Model of Schizophrenia

“…A similar non-linear relationship was observed in schizophrenia but with increases at low working memory loads and a decrease in metabolic activity with loads that would engage the PFC of control subjects (Manoach 2003). The PFC metabolic responses to different intensities of VTA stimulation were tested in both sham and NVHL animals with cytochrome oxidase I staining, revealing a leftward shift only in post-pubertal animals that had received a bilateral NVHL (Tseng et al 2006a). A functional magnetic resonance imaging study has also revealed increased blood flow in several brain regions, including the PFC, in NVHL animals (Risterucci et al 2005).…”

“…A deficit in PFC interneurons has indeed been suggested by the selective downregulation of glutamate decarboxylase-67 messenger RNA in the PFC of NVHL animals (Lipska et al 2003a(Lipska et al , 2003b. This, compounded by the abnormal potentiation of D 1 and NMDA responses and the attenuation of D 2 inhibition of AMPA responses, would yield a hyper-reactive PFC in NVHL animals, especially in response to mesocortical stimulation Tseng et al 2006a). Thus, PFC DA-GABA-glutamate interactions are compromised in animals that received an early inactivation of the hippocampal formation.…”

“…This context-dependent DA increase will activate both D 1 and D 2 receptors, with D 1 activation facilitating ongoing NMDA activity (Tseng and O'Donnell 2005;Wang and O'Donnell 2001) and both D 1 and D 2 activation reducing irrelevant excitatory inputs by increasing local inhibitory tone (Goldman-Rakic et al 2000;Gorelova et al 2002;O'Donnell 2004, 2006;Tseng et al 2006b) and reducing pyramidal neuron excitability in response to mesocortical stimulation (Lewis and O'Donnell 2000;Tseng et al 2006b). The abnormal excitation by D 1 and NMDA along with the lack of D 2 -mediated inhibition of AMPA and NMDA effects in the PFC of NVHL animals might contribute to establish the altered PFC electrophysiological and metabolic (Tseng et al 2006a) responses observed in these animals. A disruption of DA-mediated inhibition might result in abnormal and inappropriate engagement of pyramidal neuron firing in response to excitatory inputs, which ultimately might lead to altered cognitive performance in NVHL animals (Chambers et al 1999), a model proposed to mimic some of the cortical deficits observed in schizophrenia (Lipska and Weinberger 1998).…”

MRI and X-ray scanning images of the brain of 3-, 6- and 9-month-old rats with bilateral neonatal ventral hippocampus lesions

“…We examined 33 rats with a bilateral ventral hippocampal lesion with substantial rostro-caudal extension, similar to other such studies (Chambers et al, 1996;Becker et al, 1999;Khaing et al, 2000;Swerdlow et al, 2001;Goto and O'Donnell, 2002;Le Pen and Moreau, 2002;O'Donnell et al, 2002;Bhardwaj et al, 2003;Le Pen et al, 2003;Wood et al, 2003;Laplante et al, 2004Laplante et al, , 2005Flores et al, 2005;Risterucci et al, 2005;Conroy et al, 2007;Tseng et al, 2006Tseng et al, , 2007Tseng et al, , 2008Tseng et al, , 2009Bertrand et al, ). This was concluded from the histological aspect of the lesions (not shown).…”

NMDAR antagonist action in thalamus imposes delta oscillations on the hippocampus

“…Recent work shows that there is hyperactivity of CA1 in this model and that this hyperactivity affects downstream processes Grace 2007, 2011). Notably, the hippocampus can activate the dopamine system via polysynaptic pathways (Lodge and Grace 2011), which, in turn, affects prefrontal function (Tseng et al 2006). Importantly, a high-resolution study of the hippocampal blood oxygenation level-dependent (BOLD) signal in schizophrenia shows a particularly strong activation in CA1 (Schobel et al 2009).…”