A Brain without Brakes: Reduced Inhibition Is Associated with Enhanced but Dysregulated Plasticity in the Aged Rat Auditory Cortex

Abstract

During early developmental windows known as critical periods (CPs) of plasticity, passive alterations in the quality and quantity of sensory inputs are sufficient to induce profound and long-lasting distortions in cortical sensory representations. With CP closure, those representations are stabilized, a process requiring the maturation of inhibitory networks and the maintenance of sufficient GABAergic tone in the cortex. In humans and rodents, however, cortical inhibition progressively decreases with advancing age, raising the possibility that the regulation of plasticity could be altered in older individuals. Here we tested the hypothesis that aging results in a destabilization of sensory representations and maladaptive dysregulated plasticity in the rat primary auditory cortex (A1). Consistent with this idea, we found that passive tone exposure is sufficient to distort frequency tuning in the A1 of older but not younger adult rats. However, we also found that these passive distortions decayed rapidly, indicating an ongoing instability of A1 tuning in the aging cortex. These changes were associated with a decrease in GABA neurotransmitter concentration and a reduction in parvalbumin and perineuronal net expression in the cortex. Finally, we show that artificially increasing GABA tone in the aging A1 is sufficient to restore representational stability and improve the retention of learning.

Top‐down or bottom up: decreased stimulus salience increases responses to predictable stimuli of auditory thalamic neurons

“…The present findings, obtained using temporally degraded modulated sounds in young-adult MGB units, support our hypothesis that modelled ageing using temporally degraded stimuli in young rats. These findings are consistent with studies showing an age-related increase in predictable preference or an increase in firing with repetition (de Villers-Sidani et al 2010;Cai et al 2016;Cisneros-Franco et al 2018). We postulated this to be the result of a temporally jittered/less salient code in aged MGB that frequently led to increases in firing with repetition.…”

“…A second ageing MGB study by Cai et al (2016) used complex longer duration SAM stimuli stepped between 2 and 1024 f m and found significant age-related changes in the response properties of MGB neurons when a random presentation was compared with a predictable/repeating presentation of stimuli. These findings are consistent with studies performed in aged rat auditory cortex showing a decrease in SSA (de Villers-Sidani et al 2010;Cisneros-Franco et al 2018). The use of a relatively long SAM stimulus is more complex than the short pure tones used in most SSA studies and may more closely represent animal vocalizations and human speech.…”

“…By contrast to this compensatory strategy for enhancement, in young animals, neural representations of repeating stimuli are reduced and adapted with respect to the detection of novel stimuli (i.e. SSA) (Strange, 1989;Ohl et al 1999;Ono et al 2006;Davis & Johnsrude, 2007;Fritz et al 2007;Shinn-Cunningham & Wang, 2008;Tremblay et al 2010;Duque et al 2013;Obleser, 2014;Skoe et al 2014;Malmierca et al 2015;Cisneros-Franco et al 2018). Collectively, these studies suggest that adaptation may originate from lower structures (i.e.…”

Auditory temporal acuity improves with age in the male mouse auditory thalamus: A role for perineuronal nets?

“…These results have been supported by recent animal studies which showed a deleterious effect of aging at the level of the brainstem but enhanced responses to temporally varying stimuli at the level of the primary auditory cortex (Occelli et al, 2019). Different central mechanisms have been proposed to contribute to these potentially paradoxical observations, including changes in central gain as compensation for degraded auditory input (Chambers, Resnik, et al, 2016;Chambers, Salazar, & Polley, 2016), changes in cortical connectivity (Peelle, Troiani, Wingfield, & Grossman, 2010), or altered excitatory and inhibitory balance within the aged cortex (Cisneros-Franco et al, 2018;Hughes, Turner, Parrish, & Caspary, 2010;Recanzone, 2018;Stebbings et al, 2016). However, the effect of age-related changes on the medial geniculate body (MGB, the principal region of the auditory thalamus), which is directly connected to both the IC and the auditory cortex (see Figure 1), has not been considered.…”

“…Such suggestions are supported by electrophysiological data, associating communication problems with temporal processing deficits within the auditory brainstem (Caspary, Hughes, Schatteman, & Turner, 2006;Caspary, Schatteman, & Hughes, 2005), midbrain (Parthasarathy & Bartlett, 2011;Presacco, Simon, & Anderson, 2016a, 2016bWalton, Frisina, & O'Neill, 1998), or cortex (Mendelson & Ricketts, 2001; Presacco et al, 2016aPresacco et al, , 2016b. These age-related deficits in auditory processing throughout the central auditory pathways have been variously linked to alterations in: inhibitory signaling (Caspary, Ling, Turner, & Hughes, 2008), GABAergic transmission (Burianova, Ouda, Profant, & Syka, 2009;Cisneros-Franco, Ouellet, Kamal, & Villers-Sidani, 2018;Pal et al, 2019), cholinergic dysfunction (Sottile et al, 2017), parvalbumin positive (PV+) neurons (Cisneros-Franco et al, 2018;Gray, Engle, Rudolph, & Recanzone, 2014;Pal et al, 2019); and glial cells (Tremblay, Zettel, Ison, Allen, & Majewska, 2012). However, many studies investigating aging use old animals or animal-models of accelerated aging to investigate age-related changes within the auditory system, for example CBA/ CaJ mice beyond 80 weeks of age, C57/Bl6 mice (Sergeyenko, Lall, Liberman, & Kujawa, 2013) or Fisher Brown Norway rats (Cai, Montgomery, Graves, Caspary, & Cox, 2018).…”