Practical Bayesian Inference in Neuroscience: Or How I Learned to Stop Worrying and Embrace the Distribution.

Typical statistical practices in the biological sciences have been increasingly called into question due to difficulties in the replication of an increasing number of studies, many of which are confounded by the relative difficulty of null significance hypothesis testing designs and interpretation of p-values. Bayesian inference, representing a fundamentally different approach to hypothesis testing, is receiving renewed interest as a potential alternative or complement to traditional null significance hypothesis testing due to its ease of interpretation and explicit declarations of prior assumptions. Bayesian models are more mathematically complex than equivalent frequentist approaches, which have historically limited applications to simplified analysis cases. However, the advent of probability distribution sampling tools with exponential increases in computational power now allows for quick and robust inference under any distribution of data. Here we present a practical tutorial on the use of Bayesian inference in the context of neuroscientific studies in both rat electrophysiological and computational modeling data. We first start with an intuitive discussion of Bayes' rule and inference followed by the formulation of Bayesian-based regression and ANOVA models using data from a variety of neuroscientific studies. We show how Bayesian inference leads to easily interpretable analysis of data while providing an open-source toolbox to facilitate the use of Bayesian tools.

Characterization and closed-loop control of infrared thalamocortical stimulation produces spatially constrained single-unit responses.

Deep brain stimulation (DBS) is a powerful tool for the treatment of circuitopathy-related neurological and psychiatric diseases and disorders such as Parkinson's disease and obsessive-compulsive disorder, as well as a critical research tool for perturbing neural circuits and exploring neuroprostheses. Electrically mediated DBS, however, is limited by the spread of stimulus currents into tissue unrelated to disease course and treatment, potentially causing undesirable patient side effects. In this work, we utilize infrared neural stimulation (INS), an optical neuromodulation technique that uses near to midinfrared light to drive graded excitatory and inhibitory responses in nerves and neurons, to facilitate an optical and spatially constrained DBS paradigm. INS has been shown to provide spatially constrained responses in cortical neurons and, unlike other optical techniques, does not require genetic modification of the neural target. We show that INS produces graded, biophysically relevant single-unit responses with robust information transfer in rat thalamocortical circuits. Importantly, we show that cortical spread of activation from thalamic INS produces more spatially constrained response profiles than conventional electrical stimulation. Owing to observed spatial precision of INS, we used deep reinforcement learning (RL) for closed-loop control of thalamocortical circuits, creating real-time representations of stimulus-response dynamics while driving cortical neurons to precise firing patterns. Our data suggest that INS can serve as a targeted and dynamic stimulation paradigm for both open and closed-loop DBS.

Neurometric amplitude modulation detection in the inferior colliculus of Young and Aged rats.

Amplitude modulation is an important acoustic cue for sound discrimination, and humans and animals are able to detect small modulation depths behaviorally. In the inferior colliculus (IC), both firing rate and phase-locking may be used to detect amplitude modulation. How neural representations that detect modulation change with age are poorly understood, including the extent to which age-related changes may be attributed to the inherited properties of ascending inputs to IC neurons. Here, simultaneous measures of local field potentials (LFPs) and single-unit responses were made from the inferior colliculus of Young and Aged rats using both noise and tone carriers in response to sinusoidally amplitude-modulated sounds of varying depths. We found that Young units had higher firing rates than Aged for noise carriers, whereas Aged units had higher phase-locking (vector strength), especially for tone carriers. Sustained LFPs were larger in Young animals for modulation frequencies 8-16 Hz and comparable at higher modulation frequencies. Onset LFP amplitudes were much larger in Young animals and were correlated with the evoked firing rates, while LFP onset latencies were shorter in Aged animals. Unit neurometric thresholds by synchrony or firing rate measures did not differ significantly across age and were comparable to behavioral thresholds in previous studies whereas LFP thresholds were lower than behavior.

Rapid and objective assessment of auditory temporal processing using dynamic amplitude-modulated stimuli.

Auditory neural coding of speech-relevant temporal cues can be noninvasively probed using envelope following responses (EFRs), neural ensemble responses phase-locked to the stimulus amplitude envelope. EFRs emphasize different neural generators, such as the auditory brainstem or auditory cortex, by altering the temporal modulation rate of the stimulus. EFRs can be an important diagnostic tool to assess auditory neural coding deficits that go beyond traditional audiometric estimations. Existing approaches to measure EFRs use discrete amplitude modulated (AM) tones of varying modulation frequencies, which is time consuming and inefficient, impeding clinical translation. Here we present a faster and more efficient framework to measure EFRs across a range of AM frequencies using stimuli that dynamically vary in modulation rates, combined with spectrally specific analyses that offer optimal spectrotemporal resolution. EFRs obtained from several species (humans, Mongolian gerbils, Fischer-344 rats, and Cba/CaJ mice) showed robust, high-SNR tracking of dynamic AM trajectories (up to 800Hz in humans, and 1.4 kHz in rodents), with a fivefold decrease in recording time and thirtyfold increase in spectrotemporal resolution. EFR amplitudes between dynamic AM stimuli and traditional discrete AM tokens within the same subjects were highly correlated (94% variance explained) across species. Hence, we establish a time-efficient and spectrally specific approach to measure EFRs. These results could yield novel clinical diagnostics for precision audiology approaches by enabling rapid, objective assessment of temporal processing along the entire auditory neuraxis.

Practical Bayesian Inference in Neuroscience: Or How I Learned To Stop Worrying and Embrace the Distribution.

Typical statistical practices in the biological sciences have been increasingly called into question due to difficulties in replication of an increasing number of studies, many of which are confounded by the relative difficulty of null significance hypothesis testing designs and interpretation of p-values. Bayesian inference, representing a fundamentally different approach to hypothesis testing, is receiving renewed interest as a potential alternative or complement to traditional null significance hypothesis testing due to its ease of interpretation and explicit declarations of prior assumptions. Bayesian models are more mathematically complex than equivalent frequentist approaches, which have historically limited applications to simplified analysis cases. However, the advent of probability distribution sampling tools with exponential increases in computational power now allows for quick and robust inference under any distribution of data. Here we present a practical tutorial on the use of Bayesian inference in the context of neuroscientific studies. We first start with an intuitive discussion of Bayes' rule and inference followed by the formulation of Bayesian-based regression and ANOVA models using data from a variety of neuroscientific studies. We show how Bayesian inference leads to easily interpretable analysis of data while providing an open-source toolbox to facilitate the use of Bayesian tools.

Suppressing fear in the presence of a safety cue requires infralimbic cortical signaling to central amygdala.

Stressful events can have lasting and impactful effects on behavior, especially by disrupting normal regulation of fear and reward processing. Accurate discrimination among environmental cues predicting threat, safety or reward adaptively guides behavior. Post-traumatic stress disorder (PTSD) represents a condition in which maladaptive fear persists in response to explicit safety-predictive cues that coincide with previously learned threat cues, but without threat being present. Since both the infralimbic cortex (IL) and amygdala have each been shown to be important for fear regulation to safety cues, we tested the necessity of specific IL projections to the basolateral amygdala (BLA) or central amygdala (CeA) during safety recall. Male Long Evans rats were used since prior work showed female Long Evans rats did not acquire the safety discrimination task used in this study. Here, we show the infralimbic projection to the central amygdala was necessary for suppressing fear cue-induced freezing in the presence of a learned safety cue, and the projection to the basolateral amygdala was not. The loss of discriminative fear regulation seen specifically during IL->CeA inhibition is similar to the behavioral disruption seen in PTSD individuals that fail to regulate fear in the presence of a safety cue.

Spatially specific, closed-loop infrared thalamocortical deep brain stimulation.

Deep brain stimulation (DBS) is a powerful tool for the treatment of circuitopathy-related neurological and psychiatric diseases and disorders such as Parkinson's disease and obsessive-compulsive disorder, as well as a critical research tool for perturbing neural circuits and exploring neuroprostheses. Electrically-mediated DBS, however, is limited by the spread of stimulus currents into tissue unrelated to disease course and treatment, potentially causing undesirable patient side effects. In this work, we utilize infrared neural stimulation (INS), an optical neuromodulation technique that uses near to mid-infrared light to drive graded excitatory and inhibitory responses in nerves and neurons, to facilitate an optical and spatially constrained DBS paradigm. INS has been shown to provide spatially constrained responses in cortical neurons and, unlike other optical techniques, does not require genetic modification of the neural target. We show that INS produces graded, biophysically relevant single-unit responses with robust information transfer in thalamocortical circuits. Importantly, we show that cortical spread of activation from thalamic INS produces more spatially constrained response profiles than conventional electrical stimulation. Owing to observed spatial precision of INS, we used deep reinforcement learning for closed-loop control of thalamocortical circuits, creating real-time representations of stimulus-response dynamics while driving cortical neurons to precise firing patterns. Our data suggest that INS can serve as a targeted and dynamic stimulation paradigm for both open and closed-loop DBS.

Bronchiolitis Simulation Module in the Pediatric Preclerkship Educational Exercises (PRECEDE) Curriculum.

Introduction: Acute bronchiolitis is a viral infection infecting 90% of children under the age of 2 years, with approximately 200,000 deaths per year. The current standard of care remains largely respiratory support and prevention. Therefore, understanding how to assess and escalate respiratory supportive care is paramount for health care providers taking care of children. Methods: We used a high-fidelity simulator to simulate an infant with progressing respiratory distress in the setting of acute bronchiolitis. The participants were pediatric clerkship medical students during their preclerkship educational exercises (PRECEDE). The students were asked to evaluate and treat the simulated patient. After debriefing, the students repeated the simulation. We assessed both performances via a weighted checklist specifically developed for this case to measure team performance. Students also completed an overall course evaluation. Results: Ninety out of 121 pediatric clerkship students were enrolled. Performance improved from 57% to 86% ( p < .05). Donning appropriate personal protection equipment was the most missed item both pre- and postdebriefing. Overall, the course was well liked and received. Participants requested more simulation opportunities within PRECEDE as well as a summary document to reinforce learning. Discussion: Pediatric clerkship students improved their performance managing progressing respiratory distress due to acute bronchiolitis via a performance-based assessment tool with sound validity evidence. Improvements going forward include improving faculty diversity and offering more simulation opportunities.

PARP1 proximity proteomics reveals interaction partners at stressed replication forks.

PARP1 mediates poly-ADP-ribosylation of proteins on chromatin in response to different types of DNA lesions. PARP inhibitors are used for the treatment of BRCA1/2-deficient breast, ovarian, and prostate cancer. Loss of DNA replication fork protection is proposed as one mechanism that contributes to the vulnerability of BRCA1/2-deficient cells to PARP inhibitors. However, the mechanisms that regulate PARP1 activity at stressed replication forks remain poorly understood. Here, we performed proximity proteomics of PARP1 and isolation of proteins on stressed replication forks to map putative PARP1 regulators. We identified TPX2 as a direct PARP1-binding protein that regulates the auto-ADP-ribosylation activity of PARP1. TPX2 interacts with DNA damage response proteins and promotes homology-directed repair of DNA double-strand breaks. Moreover, TPX2 mRNA levels are increased in BRCA1/2-mutated breast and prostate cancers, and high TPX2 expression levels correlate with the sensitivity of cancer cells to PARP-trapping inhibitors. We propose that TPX2 confers a mitosis-independent function in the cellular response to replication stress by interacting with PARP1.

Comparison of age-related declines in behavioral auditory responses versus electrophysiological measures of amplitude modulation.

Amplitude and frequency modulations are important for speech intelligibility, especially in noise. Neurophysiological responses assessed by envelope following responses (EFRs) are smaller at faster amplitude modulation frequencies (AMF) in older subjects compared to younger subjects. A typical assumption is that a decline in EFRs necessarily results in corresponding perceptual deficits. To test this in an animal model, we investigated the behavioral AMF discrimination of young and aged Fischer-344 rats and compared those abilities to their EFRs. A modified version of prepulse inhibition of the acoustic startle reflex was used to measure behavior. When AMF differences and modulation depths were large, young and aged animals' behavioral performances were comparable. Aged animals' discrimination abilities declined as the difference between background and prepulse AMF decreased and as modulation depth decreased. These declines were larger than in younger animals, even compared to young rats with similar peripheral activation (ABR wave I amplitudes), whose EFR amplitudes were smaller than the aged animals. The results revealed larger age-related deficits in behavioral perception compared to EFRs, suggesting additional factors that affect perception in aging.

Corticothalamic projections deliver enhanced responses to medial geniculate body as a function of the temporal reliability of the stimulus.

Ageing and challenging signal-in-noise conditions are known to engage the use of cortical resources to help maintain speech understanding. Extensive corticothalamic projections are thought to provide attentional, mnemonic and cognitive-related inputs in support of sensory inferior colliculus (IC) inputs to the medial geniculate body (MGB). Here we show that a decrease in modulation depth, a temporally less distinct periodic acoustic signal, leads to a jittered ascending temporal code, changing MGB unit responses from adapting responses to responses showing repetition enhancement, posited to aid identification of important communication and environmental sounds. Young-adult male Fischer Brown Norway rats, injected with the inhibitory opsin archaerhodopsin T (ArchT) into the primary auditory cortex (A1), were subsequently studied using optetrodes to record single-units in MGB. Decreasing the modulation depth of acoustic stimuli significantly increased repetition enhancement. Repetition enhancement was blocked by optical inactivation of corticothalamic terminals in MGB. These data support a role for corticothalamic projections in repetition enhancement, implying that predictive anticipation could be used to improve neural representation of weakly modulated sounds. KEY POINTS: In response to a less temporally distinct repeating sound with low modulation depth, medial geniculate body (MGB) single units show a switch from adaptation towards repetition enhancement. Repetition enhancement was reversed by blockade of MGB inputs from the auditory cortex. Collectively, these data argue that diminished acoustic temporal cues such as weak modulation engage cortical processes to enhance coding of those cues in auditory thalamus.

Longitudinal auditory pathophysiology following mild blast-induced trauma.

Blast-induced hearing difficulties affect thousands of veterans and civilians. The long-term impact of even a mild blast exposure on the central auditory system is hypothesized to contribute to lasting behavioral complaints associated with mild blast traumatic brain injury (bTBI). Although recovery from mild blast has been studied separately over brief or long time windows, few, if any, studies have investigated recovery longitudinally over short-term and longer-term (months) time windows. Specifically, many peripheral measures of auditory function either recover or exhibit subclinical deficits, masking deficits in processing complex, real-world stimuli that may recover differently. Thus, examining the acute time course and pattern of neurophysiological impairment using appropriate stimuli is critical to better understanding and intervening in bTBI-induced auditory system impairments. Here, we compared auditory brainstem response, middle-latency auditory-evoked potentials, and envelope following responses. Stimuli were clicks, tone pips, amplitude-modulated tones in quiet and in noise, and speech-like stimuli (iterated rippled noise pitch contours) in adult male rats subjected to mild blast and sham exposure over the course of 2 mo. We found that blast animals demonstrated drastic threshold increases and auditory transmission deficits immediately after blast exposure, followed by substantial recovery during the window of 7-14 days postblast, although with some deficits remaining even after 2 mo. Challenging conditions and speech-like stimuli can better elucidate mild bTBI-induced auditory deficit during this period. Our results suggest multiphasic recovery and therefore potentially different time windows for treatment, and deficits can be best observed using a small battery of sound stimuli.NEW & NOTEWORTHY Few studies on blast-induced hearing deficits go beyond simple sounds and sparsely track postexposure. Therefore, the recovery arc for potential therapies and real-world listening is poorly understood. Evidence suggested multiple recovery phases over 2 mo postexposure. Hearing thresholds largely recovered within 14 days and partially explained recovery. However, midlatency responses, responses to amplitude modulation in noise, and speech-like pitch sweeps exhibited extended changes, implying persistent central auditory deficits and the importance of subclinical threshold shifts.

In vivo whole-cell recordings of stimulus-specific adaptation in the inferior colliculus.

The inferior colliculus is an auditory structure where inputs from multiple lower centers converge, allowing the emergence of complex coding properties of auditory information such as stimulus-specific adaptation. Stimulus-specific adaptation is the adaptation of neuronal responses to a specific repeated stimulus, which does not entirely generalize to other new stimuli. This phenomenon provides a mechanism to emphasize saliency and potentially informative sensory inputs. Stimulus-specific adaptation has been traditionally studied analyzing the somatic spiking output. However, studies that correlate within the same inferior colliculus neurons their intrinsic properties, subthreshold responses and the level of acoustic stimulus-specific adaptation are still pending. For this, we recorded in vivo whole-cell patch-clamp neurons in the mouse inferior colliculus while stimulating with current injections or the classic auditory oddball paradigm. Our data based on cases of ten neuron, suggest that although passive properties were similar, intrinsic properties differed between adapting and non-adapting neurons. Non-adapting neurons showed a sustained-regular firing pattern that corresponded to central nucleus neurons and adapting neurons at the inferior colliculus cortices showed variable firing patterns. Our current results suggest that synaptic stimulus-specific adaptation was variable and could not be used to predict the presence of spiking stimulus-specific adaptation. We also observed a small trend towards hyperpolarized membrane potentials in adapting neurons and increased synaptic inhibition with consecutive stimulus repetitions in all neurons. This finding indicates a more simple type of adaptation, potentially related to potassium conductances. Hence, these data represent a modest first step in the intracellular study of stimulus-specific adaptation in inferior colliculus neurons in vivo that will need to be expanded with pharmacological manipulations to disentangle specific ionic channels participation.

Short-wave Infrared Neural Stimulation Drives Graded Sciatic Nerve Activation Across A Continuum of Wavelengths.

Infrared neural stimulation (INS) is an optical stimulation technique which uses coherent light to stimulate nerves and neurons and which shows increased spatial selectivity compared to electrical stimulation. This could improve deep brain, high channel count, or vagus nerve stimulation. In this study, we seek to understand the wavelength dependence of INS in the near-infrared optical window. Rat sciatic nerves were excised ex vivo and stimulated with wavelengths between 700 and 900 nm. Recorded compound nerve action potentials (CNAPs) showed that stimulation was maximized in the 700 nm window despite comparable laser power levels across wavelengths. Computational models demonstrated that wavelength-based activation dependencies were not a result of passive optical properties. This data demonstrates that INS is both wavelength and power level dependent, which inform stimulation systems to actively target neural microcircuits in humans.

Post-stimulatory activity in primate auditory cortex evoked by sensory stimulation during passive listening.

Under certain circumstances, cortical neurons are capable of elevating their firing for long durations in the absence of a stimulus. Such activity has typically been observed and interpreted in the context of performance of a behavioural task. Here we investigated whether post-stimulatory activity is observed in auditory cortex and the medial geniculate body of the thalamus in the absence of any explicit behavioural task. We recorded spiking activity from single units in the auditory cortex (fields A1, R and RT) and auditory thalamus of awake, passively-listening marmosets. We observed post-stimulatory activity that lasted for hundreds of milliseconds following the termination of the acoustic stimulus. Post-stimulatory activity was observed following both adapting, sustained and suppressed response profiles during the stimulus. These response types were observed across all cortical fields tested, but were largely absent from the auditory thalamus. As well as being of shorter duration, thalamic post-stimulatory activity emerged following a longer latency than in cortex, indicating that post-stimulatory activity may be generated within auditory cortex during passive listening. Given that these responses were observed in the absence of an explicit behavioural task, post-stimulatory activity in sensory cortex may play a functional role in processes such as echoic memory and temporal integration that occur during passive listening.

Profiling of myristoylation in Toxoplasma gondii reveals an N-myristoylated protein important for host cell penetration.

N-myristoylation is a ubiquitous class of protein lipidation across eukaryotes and N-myristoyl transferase (NMT) has been proposed as an attractive drug target in several pathogens. Myristoylation often primes for subsequent palmitoylation and stable membrane attachment, however, growing evidence suggests additional regulatory roles for myristoylation on proteins. Here we describe the myristoylated proteome of Toxoplasma gondii using chemoproteomic methods and show that a small-molecule NMT inhibitor developed against related Plasmodium spp. is also functional in Toxoplasma. We identify myristoylation on a transmembrane protein, the microneme protein 7 (MIC7), which enters the secretory pathway in an unconventional fashion with the myristoylated N-terminus facing the lumen of the micronemes. MIC7 and its myristoylation play a crucial role in the initial steps of invasion, likely during the interaction with and penetration of the host cell. Myristoylation of secreted eukaryotic proteins represents a substantial expansion of the functional repertoire of this co-translational modification.

A microscopic parasite known as Toxoplasma gondii infects around 30% of the human population. Most infections remain asymptomatic, but in people with a compromised immune system, developing fetuses and people infected with particular virulent strains of the parasite, infection can be fatal. T. gondii is closely related to other parasites that also infect humans, including the one that causes malaria. These parasites have complex lifecycles that involve successive rounds of invading the cells of their hosts, growing and then exiting these cells. Signaling proteins found at specific locations within parasite cells regulate the ability of the parasites to interact with and invade host cells. Sometimes these signaling proteins are attached to membranes using lipid anchors, for example through a molecule called myristic acid. An enzyme called NMT can attach myristic acid to one end of its target proteins. The myristic acid tag can influence the ability of target proteins to bind to other proteins, or to membranes. Previous studies have found that drugs that inhibit the NMT enzyme prevent the malaria parasite from successfully invading and growing inside host cells. The NMT enzyme from T. gondii is very similar to that of the malaria parasite. Broncel et al. have shown that the drug developed against P. falciparum also inhibits the ability of T. gondii to grow. These findings suggest that drugs against the NMT enzyme may be useful to treat diseases caused by T. gondii and other closely-related parasites. Broncel et al. also identified 65 proteins in T. gondii that contain a myristic acid tag using an approach called proteomics. One of the unexpected 'myristoylated' proteins identified in the experiments is known as MIC7. This protein was found to be transported onto the surface of T. gondii parasites and is required in its myristoylated form for the parasite to successfully invade host cells. This was surprising as myristoylated proteins are generally thought to not enter the pathway that brings proteins to the outside of cell. These findings suggest that myristic acid on proteins that are secreted can facilitate interactions between cells, maybe by inserting the myristic acid into the cell membrane.

Nocodazole-Induced Expression and Phosphorylation of Anillin and Other Mitotic Proteins Are Decreased in DNA-Dependent Protein Kinase Catalytic Subunit-Deficient Cells and Rescued by Inhibition of the Anaphase-Promoting Complex/Cyclosome with proTAME but Not Apcin.

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has well-established roles in DNA double-strand break repair, and recently, nonrepair functions have also been reported. To better understand its cellular functions, we deleted DNA-PKcs from HeLa and A549 cells using CRISPR/Cas9. The resulting cells were radiation sensitive, had reduced expression of ataxia-telangiectasia mutated (ATM), and exhibited multiple mitotic defects. Mechanistically, nocodazole-induced upregulation of cyclin B1, anillin, and securin was decreased in DNA-PKcs-deficient cells, as were phosphorylation of Aurora A on threonine 288, phosphorylation of Polo-like kinase 1 (PLK1) on threonine 210, and phosphorylation of targeting protein for Xenopus Klp2 (TPX2) on serine 121. Moreover, reduced nocodazole-induced expression of anillin, securin, and cyclin B1 and phosphorylation of PLK1, Aurora A, and TPX2 were rescued by inhibition of the anaphase-promoting complex/cyclosome (APC/C) by proTAME, which prevents binding of the APC/C-activating proteins Cdc20 and Cdh1 to the APC/C. Altogether, our studies suggest that loss of DNA-PKcs prevents inactivation of the APC/C in nocodazole-treated cells.

Reversible ADP-ribosylation of RNA.

ADP-ribosylation is a reversible chemical modification catalysed by ADP-ribosyltransferases such as PARPs that utilize nicotinamide adenine dinucleotide (NAD+) as a cofactor to transfer monomer or polymers of ADP-ribose nucleotide onto macromolecular targets such as proteins and DNA. ADP-ribosylation plays an important role in several biological processes such as DNA repair, transcription, chromatin remodelling, host-virus interactions, cellular stress response and many more. Using biochemical methods we identify RNA as a novel target of reversible mono-ADP-ribosylation. We demonstrate that the human PARPs - PARP10, PARP11 and PARP15 as well as a highly diverged PARP homologue TRPT1, ADP-ribosylate phosphorylated ends of RNA. We further reveal that ADP-ribosylation of RNA mediated by PARP10 and TRPT1 can be efficiently reversed by several cellular ADP-ribosylhydrolases (PARG, TARG1, MACROD1, MACROD2 and ARH3), as well as by MACROD-like hydrolases from VEEV and SARS viruses. Finally, we show that TRPT1 and MACROD homologues in bacteria possess activities equivalent to the human proteins. Our data suggest that RNA ADP-ribosylation may represent a widespread and physiologically relevant form of reversible ADP-ribosylation signalling.

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

KEY POINTS: Temporal imprecision leads to deficits in the comprehension of signals in cluttered acoustic environments, and the elderly are shown to use cognitive resources to disambiguate these signals. To mimic ageing in young rats, we delivered sound signals that are temporally degraded, which led to temporally imprecise neural codes. Instead of adaptation to repeated stimuli, with degraded signals, there was a relative increase in firing rates, similar to that seen in aged rats. We interpret this increase with repetition as a repair mechanism for strengthening the internal representations of degraded signals by the higher-order structures. ABSTRACT: To better understand speech in challenging environments, older adults increasingly use top-down cognitive and contextual resources. The medial geniculate body (MGB) integrates ascending inputs with descending predictions to dynamically gate auditory representations based on salience and context. A previous MGB single-unit study found an increased preference for predictable sinusoidal amplitude modulated (SAM) stimuli in aged rats relative to young rats. The results suggested that the age-degraded/jittered up-stream acoustic code may engender an increased preference for predictable/repeating acoustic signals, possibly reflecting increased use of top-down resources. In the present study, we recorded from units in young-adult MGB, comparing responses to standard SAM with those evoked by less salient SAM (degraded) stimuli. We hypothesized that degrading the SAM stimulus would simulate the degraded ascending acoustic code seen in the elderly, increasing the preference for predictable stimuli. Single units were recorded from clusters of advanceable tetrodes implanted above the MGB of young-adult awake rats. Less salient SAM significantly increased the preference for predictable stimuli, especially at higher modulation frequencies. Rather than adaptation, higher modulation frequencies elicited increased numbers of spikes with each successive trial/repeat of the less salient SAM. These findings are consistent with previous findings obtained in aged rats suggesting that less salient acoustic signals engage the additional use of top-down resources, as reflected by an increased preference for repeating stimuli that enhance the representation of complex environmental/communication sounds.

Age-related Changes in Neural Coding of Envelope Cues: Peripheral Declines and Central Compensation.

Aging listeners often experience difficulties in perceiving temporally complex acoustic cues in noisy environments. These difficulties likely have neurophysiological contributors from various levels of auditory processing. Cochlear synapses between inner hair cells and auditory nerve fibers exhibit a progressive decline with age which is not reflected in the threshold audiogram. The functional consequences of this loss for the coding of suprathreshold sound remain poorly understood. Recent studies suggest that cochlear synaptopathy results in degraded representations of temporal envelope cues at the earliest levels of the auditory pathway. Central nuclei downstream of the auditory nerve exhibit a compensatory plasticity in response to this deafferentation, in the form of altered gain. This results in a modulation frequency selective increase in the representation of envelope cues at the level of the auditory midbrain and cortex. These changes may be shaped by mechanisms such as decreased inhibitory neurotransmission occurring with age across various central auditory nuclei. Altered representations of the differing temporal components of speech due to these interactions between multiple levels of the auditory pathway may contribute to the age-related difficulties hearing speech in noisy environments.