Functional networks underlying latent inhibition learning in the mouse brain

Abstract

The present study reports the first comprehensive map of brain networks underlying latent inhibition learning and the first application of structural equation modeling to cytochrome oxidase data. In latent inhibition, repeated exposure to a stimulus results in a latent form of learning that inhibits subsequent associations with that stimulus. As neuronal energy demand to form learned associations changes, so does the induction of the respiratory enzyme cytochrome oxidase. Therefore, cytochrome oxidase can be used as an endpoint metabolic marker of the effects of experience on regional brain metabolic capacity. Quantitative cytochrome oxidase histochemistry was used to map brain regions in mice trained on a tone-footshock fear conditioning paradigm with either tone preexposure (latent inhibition), conditioning only (acquisition), conditioning followed by tone alone (extinction), or no handling or conditioning (naïve). The ventral cochlear nucleus, medial geniculate, CA1 hippocampus, and perirhinal cortex showed modified metabolic capacity due to latent inhibition. Structural equation modeling was used to determine the causal influences in an anatomical network of these regions and others thought to mediate latent inhibition, including the accumbens and entorhinal cortex. An uncoupling of ascending influences between auditory regions was observed in latent inhibition. There was also a reduced influence on the accumbens from the perirhinal cortex in both latent inhibition and extinction. The results suggest a specific network with a neural mechanism of latent inhibition that appears to involve sensory gating, as evidenced by modifications in metabolic capacity and effective connectivity between auditory regions and reduced perirhinal cortex influence on the accumbens. Keywords latent inhibition; metabolic mapping; structural equation modeling; cytochrome oxidase; sensory gating; perirhinal cortex; learning and memory In latent inhibition (LI), preexposure to a stimulus inhibits subsequent associations with that stimulus (Lubow and Moore, 1959). LI has been demonstrated in several behavioral paradigms in a variety of species, including humans, and is disrupted in schizophrenics (Lubow, 1989). Lesion and pharmacological studies have explored the neural mechanisms underlying LI and have identified several key brain regions. Conditioned drink suppression and eye blink conditioning studies demonstrated that lesions to the entorhinal cortex disrupt LI (Coutureau et al., 1999;Shohamy et al., 2000;Coutureau et al., 2002). Other studies using a conditioned Correspondence should be addressed to: Prof. F. Gonzalez-Lima, University of Texas at Austin, Department of Psychology, 1 University Station A8000, Austin, TX 78712-0187, USA. Phone (512) Fax (512) 471-4728, email: gonzalez-lima@mail.utexas.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will under...

Chronic social stress in puberty alters appetitive male sexual behavior and neural metabolic activity

“…However, changes in c-fos expression reflect evoked activity, while changes in cytochrome oxidase activity represent long-term effects of stress on metabolic activity within the brain (Sakata et al, 2002). As cytochrome oxidase activity reflects cumulative neural activity (Puga et al, 2007), the data suggest that repeated social subjugation persistently reduces neural activity in these areas.…”

Cocaine reduces cytochrome oxidase activity in the prefrontal cortex and modifies its functional connectivity with brainstem nuclei

“…Group differences in mean cytochrome oxidase activity measured in each brain region were evaluated by one-way ANOVA. Functional connectivity was assessed by computing separate pair-wise Pearson correlation matrices of cytochrome oxidase activity across all regions of interest for each group (within-group analysis) (Puga et al, 2007). In this data-driven approach, all the brain regions are evaluated and the brain effects determine which are the relevant inter-regional correlations, as opposed to using a more restricted theory-driven or arbitrary selection of regions for analysis (McIntosh and Gonzalez-Lima, 1994a, 1994b).…”

“…These correlations were then tested for significant differences between groups (between-group analysis). The Fisher Z transformation was used to convert each correlation to a Z score to test differences in inter-regional correlations between groups (Jones and Gonzalez-Lima, 2001; Bruchey and Gonzalez-Lima, 2006; Puga et al, 2007). Significant group differences of pair-wise inter-regional correlations between cocaine- and vehicle-treated animals were calculated as absolute value of Z abs >1.96 ( p <0.05).…”

“…As with all functional connectivity methods, inter-regional correlations do not provide information on the direction of the influence, so they need to be interpreted based on known anatomical pathways. For example, if region A that influences region B via an anatomical path showed a significant pair-wise positive correlation in cytochrome oxidase activity after treatment, it may be inferred that a change in activity in region A was functionally related to a corresponding alteration in region B (Puga et al, 2007). The term functional connection was used to refer to jackknife-tested reliably significant cytochrome oxidase activity correlations between two brain regions (Padilla et al, 2011).…”

“…This particular functional connectivity method using inter-correlations of cytochrome oxidase activity describes stable metabolic relationships among areas, and it also describes how the regions are modified across sustained behavioral paradigms (Puga et al, 2007; Conejo et al, 2010; Fidalgo et al, 2012) or drug treatments (Padilla et al, 2011; Riha et al, 2011). Characterizing which specific neural systems modify their metabolic capacity and functional connectivity as a result of repeated cocaine exposure may advance our understanding of cocaine-enhanced locomotion.…”