Aging redistributes medial prefrontal neuronal excitability and impedes extinction of trace fear conditioning

doi:10.1016/j.neurobiolaging.2011.03.020

Neurobiology of Aging

Volume 33, Issue 8, August 2012, Pages 1744-1757

https://doi.org/10.1016/j.neurobiolaging.2011.03.020 Get rights and content

Abstract

Cognitive flexibility is critical for survival and reflects the malleability of the central nervous system (CNS) in response to changing environmental demands. Normal aging results in difficulties modifying established behaviors, which may involve medial prefrontal cortex (mPFC) dysfunction. Using extinction of conditioned fear in rats to assay cognitive flexibility, we demonstrate that extinction deficits reminiscent of mPFC dysfunction first appear during middle age, in the absence of hippocampus-dependent context deficits. Emergence of aging-related extinction deficits paralleled a redistribution of neuronal excitability across two critical mPFC regions via two distinct mechanisms. First, excitability decreased in regular spiking neurons of infralimbic-mPFC (IL), a region whose activity is required for extinction. Second, excitability increased in burst spiking neurons of prelimbic-mPFC (PL), a region whose activity hinders extinction. Experiments using synaptic blockers revealed that these aging-related differences were intrinsic. Thus, changes in IL and PL intrinsic excitability may contribute to cognitive flexibility impairments observed during normal aging.

Introduction

The wide range of cognitive deficits associated with advanced aging imply a large-scale disruption of brain systems (Andrews-Hanna et al., 2007), making the discovery of critical cellular changes in the aging brain exceedingly difficult. Basic research in animal models of aging often focus on overt learning and memory deficits associated with hippocampal malfunction (Knuttinen et al., 2001, Rapp and Amaral, 1991, Rosenzweig et al., 2003, Thompson et al., 1996). However, dysfunction of the prefrontal cortex (PFC) also emerges during the aging process (Aine et al., 2006, Nordahl et al., 2006, Salat et al., 1999, Salat et al., 2001, Salat et al., 2005, Schoenbaum et al., 2002). PFC dysfunction has been linked to aging induced impairments in executive function, such as cognitive flexibility (Chao and Knight, 1997, Head et al., 2008, Rasmussen et al., 1996). Therefore, we set out to examine cellular mechanisms underlying aging-related deficits in cognitive flexibility associated with PFC dysfunction, and thus advance studies of cellular changes associated with the initiation of brain aging.

An example of cognitive flexibility is behavioral extinction, which is the learned inhibition of a former response tendency in lieu of a new set of rules. Studies in humans (Milad et al., 2005, Milad et al., 2007) and rats (Morgan and LeDoux, 1995, Morgan et al., 1993, Quirk and Mueller, 2008, Quirk et al., 2000, Santini et al., 2008) indicate that extinction of conditioned fear is mediated by the medial PFC (mPFC). Specifically, the infralimbic-mPFC (IL) and the prelimbic-mPFC (PL) shape the extinction of conditioned fear. Increased neuronal activity within IL facilitates extinction (Burgos-Robles et al., 2007, Milad and Quirk, 2002, Quirk and Mueller, 2008), whereas PL excitation impairs extinction (Burgos-Robles et al., 2009, Vidal-Gonzalez et al., 2006).

There is consensus that aging results in a global decrease in excitability of hippocampal pyramidal neurons (Disterhoft and Oh, 2007). To date, the effect of aging on neuronal excitability in mPFC (specifically IL and PL) has yet to be explored. Given that aging may differentially affect neurons within these mPFC subregions, we examined cellular excitability of IL and PL neurons across the lifespan.

The current study provides the first characterization of behavioral deficits in trace fear extinction in middle-aged rats, which emerges prior to more global deficits associated with hippocampal dysfunction in aged rats. Together, the behavioral and electrophysiological data suggest that a decrease in excitability of regular spiking IL neurons and concomitant increase in excitability of burst spiking PL neurons begins in middle age and that these physiological changes parallel an aging-related disruption of extinction learning.

Section snippets

Subjects

Adult (3–6 mo), middle-aged (13–18 mo), and aged (22–28 mo) male F344 rats were used for all behavioral (20 adult, 19 middle-aged, 9 aged) and electrophysiological (33 adult, 14 middle-aged, 12 aged) experiments. All rats were maintained on a 14 h light/10 h dark cycle and housed individually with free access to food and water. All procedures were conducted in accordance with the University of Wisconsin-Milwaukee Animal Care and Use Committee (ACUC) and NIH guidelines.

Fear conditioning and apparatuses

The fear conditioning and

Aging deficits in cognitive flexibility (extinction) emerge prior to overt learning and memory deficits

In the present study we employed trace fear conditioning followed by extinction training in order to examine the effects of aging on behavioral extinction. Specifically, we addressed whether the effects of aging on extinction learning occur prior to, and independent of, deficits on acquisition/retention of trace fear conditioning in aged rats (McEchron et al., 2004, Moyer and Brown, 2006, Villarreal et al., 2004). This is an important distinction given that acquisition/retention of trace fear

Discussion

The present study combined trace fear conditioning and extinction with whole-cell patch-clamp recordings across the lifespan to reveal novel mechanisms underlying aging-related impairments in extinction—an index of cognitive flexibility. Aging-related extinction deficits mimic those observed in adult rats following permanent or temporary lesions of the mPFC (Morgan et al., 2003, Quirk and Mueller, 2008, Sierra-Mercado et al., 2006) and were indicative of mPFC dysfunction. We show, for the first

Disclosure statement

The authors report no real or perceived conflicts of interest.

Acknowledgments

Supported by a University of Wisconsin-Milwaukee Research Growth Initiative (JRM) and Quincy Bioscience (JRM). The authors thank Shannon Moore and Chenghui Song for critical comments on the manuscript and Caroline Cook for advice on the illustrations.

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Like synaptic plasticity, intrinsic plasticity in measures such as the post-burst afterhyperpolarization or firing rate occurs throughout the brain and has been most extensively studied in CA1 pyramidal neurons, where it modulates strength of several hippocampal-dependent associative and learning memory tasks (Disterhoft, Coulter, & Alkon, 1986; Disterhoft, Golden, Read, Coulter, & Alkon, 1988; Dunn et al., 2018; Kaczorowski & Disterhoft, 2009; Matthews, Weible, Shah, & Disterhoft, 2008; McEchron & Disterhoft, 1997; McEchron, Tseng, & Disterhoft, 2003; McKay, Matthews, Oliveira, & Disterhoft, 2009; McKay, Oh, & Disterhoft, 2013; Moyer, Thompson, & Disterhoft, 1996; Neuner et al., 2015; Oh, Kuo, Wu, Sametsky, & Disterhoft, 2003; Weiss, Kronfrost-Collins, & Disterhoft, 1996). Also like LTP, reports in the literature regarding learning-relating changes in intrinsic plasticity differ depending on both stimulation paradigm and recording paradigm, indices of neuronal excitability (e.g., firing rate versus post-spike afterhyperpolarization), genetic background, brain region, and cell type (Disterhoft et al., 1986, 1988; Kaczorowski, Disterhoft, & Spruston, 2007; Kaczorowski, Davis, & Moyer, 2012; Kaczorowski, 2011; McEchron & Disterhoft, 1997; McEchron et al., 2003; Moore, Throesch, & Murphy, 2011; Neuner, Ding, & Kaczorowski, 2019; Oh, Simkin, & Disterhoft, 2016; Sehgal, Ehlers, & Moyer, 2014), though our understanding of how to integrate these disparate findings into a single working model of intrinsic plasticity is not yet complete. Finally, both reduced intrinsic excitability and impaired intrinsic plasticity in key brain regions such as CA1 of the hippocampus occur in aging and Alzheimer’s disease (AD) and are associated with cognitive deficits (Eslamizade et al., 2015; Kaczorowski & Disterhoft, 2009; Kaczorowski, Sametsky, Shah, Vassar, & Disterhoft, 2011; Knuttinen, Gamelli, Weiss, Power, & Disterhoft, 2001; Matthews, Linardakis, & Disterhoft, 2009; McEchron, Weible, & Disterhoft, 2001; Neuner et al., 2015; Oh & Disterhoft, 2010; Power, Wu, Sametsky, Oh, & Disterhoft, 2002; Tombaugh, Rowe, & Rose, 2005), though pathological hyperexcitablity is also reported as a feature of AD (Amatniek et al., 2006; Brown, Chin, Leiser, Pangalos, & Randall, 2011; Haberman, Koh, & Gallagher, 2017; Kerrigan, Brown, & Randall, 2014; Oh et al., 2016; Scala et al., 2015; Simkin et al., 2015; Vossel et al., 2013).
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Cognitive flexibility is supported by the dorsolateral prefrontal cortex in humans (Demakis, 2003; Owen, Roberts, Polkey, Sahakian, & Robbins, 1991) and other primates (Dias, Robbins, & Roberts, 1996a, 1996b; Moore, Schettler, Killiany, Rosene, & Moss, 2009), and the homologous medial prefrontal cortex (mPFC) in rodents (Birrell & Brown, 2000; Bissonette & Powell, 2012; Floresco, Block, & Tse, 2008; Uylings, Groenewegen, & Kolb, 2003). Specifically, the ability to extinguish a cue-driven behavior, one measure of cognitive flexibility, is mediated by increased neuronal activity within the infralimbic region of the rodent mPFC (Burgos-Robles, Vidal-Gonzalez, Santini, & Quirk, 2007; Milad & Quirk, 2002; Quirk & Mueller, 2008), and age-related decreases in the excitability of these neurons have been linked to flexibility impairments in old animals (Kaczorowski, Davis, & Moyer, 2012). While the prefrontal cortex, and mPFC in particular, is unequivocally involved in behavioral flexibility (Logue & Gould, 2014), this brain region does not act in isolation to update response selection.
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: Current affiliations: C.C. Kaczorowski: Department of Physiology, Medical College of Wisconsin, Milwaukee WI 53226, USA; S.J. Davis: Institute for Neuroscience, University of Texas at Austin, Austin TX 78712, USA

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Regular paperAging redistributes medial prefrontal neuronal excitability and impedes extinction of trace fear conditioning

Abstract

Introduction

Section snippets

Subjects

Fear conditioning and apparatuses

Aging deficits in cognitive flexibility (extinction) emerge prior to overt learning and memory deficits

Discussion

Disclosure statement

Acknowledgments

Neuroimage

Neuron

Neurobiol. Aging

Neuron

Brain Cogn.

Trends Neurosci.

Pharmacol. Biochem. Behav

Neurobiol. Aging

Behav. Brain Res

Neurobiol. Learn Mem

Neurobiol. Aging

Neuropharmacology

Life Sci.

Trends Neurosci.

Brain Res Rev

Prog. Neurobiol

Neurobiol Learn Mem

Biol. Psychiatry

Neurosci. Lett

Behav. Brain Res

Neuron

Neuron

Behav. Brain Res

Neuron

Neurobiol. Aging

Neurobiol. Aging

Neuron

Trends Neurosci.

Reduced potassium currents in old rat CA1 hippocampal neurons

J. Neurosci. Res

Ionic basis of spike after-depolarization and burst generation in adult rat hippocampal CA1 pyramidal cells

J. Physiol

Aged rats are impaired on an attentional set-shifting task sensitive to medial frontal cortex damage in young rats

Learn. Mem

Crouching as an index of fear

J. Comp. Physiol. Psychol

A synaptic model of memory: long-term potentiation in the hippocampus

Nature

Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure

J. Neurosci

Temporally massed CS presentations generate more fear extinction than spaced presentations

J. Exp. Psychol. Anim. Behav. Process

Aging changes in voltage-gated calcium currents in hippocampal CA1 neurons

J. Neurosci

Single-unit activity in the medial prefrontal cortex during immediate and delayed extinction of fear in rats

PLoS ONE

Prefrontal deficits in attention and inhibitory control with aging

Cereb. Cortex

Expression of alpha 1D subunit mRNA is correlated with L-type Ca2+ channel activity in single neurons of hippocampal “zipper” slices

Proc. Natl. Acad. Sci. U. S. A.

Dorsal hippocampus involvement in trace fear conditioning with long, but not short, trace intervals in mice

Behav. Neurosci

Electrophysiological properties of neocortical neurons in vitro

J. Neurophysiol

Overexpression of hAPPswe impairs rewarded alternation and contextual fear conditioning in a transgenic mouse model of Alzheimer's disease

Learn. Mem

Activity in prelimbic cortex is necessary for the expression of learned, but not innate, fears

J. Neurosci

Electrophysiological properties of pyramidal neurons in the rat prefrontal cortex: an in vivo intracellular recording study

Cereb. Cortex

Differential effects of training intertrial interval on acquisition of trace and long-delay fear conditioning in rats

Behav. Neurosci

Changes in the structural complexity of the aged brain

Aging Cell

Alterations in intrinsic neuronal excitability during normal aging

Aging Cell

Decreased duration of Ca(2+)-mediated plateau potentials in striatal neurons from aged rats

J. Neurophysiol

Lesions of the dorsal hippocampus block trace fear conditioned potentiation of startle

Behav. Neurosci

Regular paper
Aging redistributes medial prefrontal neuronal excitability and impedes extinction of trace fear conditioning