Presynaptic Neuronal Nicotinic Receptors Differentially Shape Select Inputs to Auditory Thalamus and Are Negatively Impacted by Aging

Abstract

Acetylcholine (ACh) is a potent neuromodulator capable of modifying patterns of acoustic information flow. In auditory cortex, cholinergic systems have been shown to increase salience/gain while suppressing extraneous information. However, the mechanism by which cholinergic circuits shape signal processing in the auditory thalamus (medial geniculate body, MGB) is poorly understood. The present study, in male Fischer Brown Norway rats, seeks to determine the location and function of presynaptic neuronal nicotinic ACh receptors (nAChRs) at the major inputs to MGB and characterize how nAChRs change during aging. In vitro electrophysiological/optogenetic methods were used to examine responses of MGB neurons after activation of nAChRs during a paired-pulse paradigm. Presynaptic nAChR activation increased responses evoked by stimulation of excitatory corticothalamic and inhibitory tectothalamic terminals. Conversely, nAChR activation appeared to have little effect on evoked responses from inhibitory thalamic reticular nucleus and excitatory tectothalamic terminals. In situ hybridization data showed nAChR subunit transcripts in GABAergic inferior colliculus neurons and glutamatergic auditory cortical neurons supporting the present slice findings. Responses to nAChR activation at excitatory corticothalamic and inhibitory tectothalamic inputs were diminished by aging. These findings suggest that cholinergic input to the MGB increases the strength of tectothalamic inhibitory projections, potentially improving the signal-to-noise ratio and signal detection while increasing corticothalamic gain, which may facilitate top-down identification of stimulus identity. These mechanisms appear to be affected negatively by aging, potentially diminishing speech perception in noisy environments. Cholinergic inputs to the MGB appear to maximize sensory processing by adjusting both top-down and bottom-up mechanisms in conditions of attention and arousal.

Inhibitory Projections from the Inferior Colliculus to the Medial Geniculate body Originate from Four Subtypes of GABAergic Cells

“…GABAergic subtypes with or without PNs could be expected to show different degrees of plasticity, perhaps related to signal salience or top-down modulation of the auditory brainstem, or effects of neuromodulatory inputs ( Schofield and Hurley, 2018 ). Sottile et al (2017a , b ) demonstrated nicotinic receptors associated with GABAergic tectothalamic projections, and showed further that these receptors can change during aging. The authors commented on nicotinic receptor subunits expressed in the large GABAergic IC cells, but also showed evidence for such expression in smaller GABAergic cells.…”

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

“…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).…”

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

“…These results support our stimulus choice aimed at simulating temporal processing deficits observed with ageing, which are partly mediated by neurotransmitter-deficits with ageing. Age-related changes in neurotransmission impact upon the function of descending and ascending projections to the MGB, which include decreased tonic GABA currents, as well as preand post-synaptic changes in cholinergic receptors, and are considered to be involved in gating/modulating MGB representations (Banay- Schwartz et al 1989;Richardson et al 2013b;Godfrey et al 2017;Sottile et al 2017a;Sottile et al 2017b). However, Richardson et al (2013a) failed to find evidence of age-related physiological changes in MGB function using short duration pure tone SSA paradigm (Richardson et al 2013a).…”

“…They found a gain in MGB activity that lasted for 150 ms post-stimulation, which was associated with enhanced sound detection (Guo et al 2017). Few studies have investigated the effect of corticothalamic stimulation with ageing on MGB physiology (Sottile et al 2017a;Sottile et al 2017b). Apart from modulating MGB response properties, corticothalamic projections are implicated in the switching from temporal to rate code, possibly involving some combination of short-term NMDA/AMPA and long-term mGluR-dependent mechanisms (Lu et al 2001;Bartlett & Smith, 2002;Bartlett & Wang, 2007;Wang et al 2008;Rabang & Bartlett, 2011;Cai & Caspary, 2015).…”

“…The ventral division is lemniscal in nature, projecting principally to layers 3/4, whereas the dorsal and medial subdivisions receive inputs from dorsal and external cortices of the inferior colliculus, tegmentum, superior colliculus and spinal cord considered to be extra-lemniscal and projecting to layers 1 and 6 of the primary auditory cortex, as well as belt areas of the auditory cortex and amygdala, amongst others (Winer et al 2005;de la Mothe et al 2006;Bartlett, 2013). The MGB also receives cholinergic projections that may further engage top-down resources providing cognitive and attentional resources that shape the ascending code (Rouiller & Welker, 1991;Winer et al 2001;Bartlett & Smith, 2002;He, 2003;Bartlett, 2013;Malmierca et al 2015;Guo et al 2017;Lesicko & Llano, 2017;Sottile et al 2017a;Sottile et al 2017b;Schofield & Hurley, 2018). The MGB also receives tectothalamic inputs that carry ascending sensory inputs and shows stimulus-specific adaptation (SSA) to repeating stimuli, facilitating the detection of novel stimuli (Nelken, 2014;Malmierca et al 2015), comprising a property considered to be of bottom-up origin, independent of age and even enhanced by anaesthesia (Ulanovsky et al 2003;von der Behrens et al 2009;Richardson et al 2013a;Malmierca et al 2015;Nir et al 2015).…”