Corrigendum: Increased central auditory gain in 5xFAD Alzheimer's disease mice as an early biomarker candidate for Alzheimer's disease diagnosis.

[This corrects the article DOI: 10.3389/fnins.2023.1106570.].

Increased central auditory gain in 5xFAD Alzheimer's disease mice as an early biomarker candidate for Alzheimer's disease diagnosis.

Alzheimer's Disease (AD) is a neurodegenerative illness without a cure. All current therapies require an accurate diagnosis and staging of AD to ensure appropriate care. Central auditory processing disorders (CAPDs) and hearing loss have been associated with AD, and may precede the onset of Alzheimer's dementia. Therefore, CAPD is a possible biomarker candidate for AD diagnosis. However, little is known about how CAPD and AD pathological changes are correlated. In the present study, we investigated auditory changes in AD using transgenic amyloidosis mouse models. AD mouse models were bred to a mouse strain commonly used for auditory experiments, to compensate for the recessive accelerated hearing loss on the parent background. Auditory brainstem response (ABR) recordings revealed significant hearing loss, a reduced ABR wave I amplitude, and increased central gain in 5xFAD mice. In comparison, these effects were milder or reversed in APP/PS1 mice. Longitudinal analyses revealed that in 5xFAD mice, central gain increase preceded ABR wave I amplitude reduction and hearing loss, suggesting that it may originate from lesions in the central nervous system rather than the peripheral loss. Pharmacologically facilitating cholinergic signaling with donepezil reversed the central gain in 5xFAD mice. After the central gain increased, aging 5xFAD mice developed deficits for hearing sound pips in the presence of noise, consistent with CAPD-like symptoms of AD patients. Histological analysis revealed that amyloid plaques were deposited in the auditory cortex of both mouse strains. However, in 5xFAD but not APP/PS1 mice, plaque was observed in the upper auditory brainstem, specifically the inferior colliculus (IC) and the medial geniculate body (MGB). This plaque distribution parallels histological findings from human subjects with AD and correlates in age with central gain increase. Overall, we conclude that auditory alterations in amyloidosis mouse models correlate with amyloid deposits in the auditory brainstem and may be reversed initially through enhanced cholinergic signaling. The alteration of ABR recording related to the increase in central gain prior to AD-related hearing disorders suggests that it could potentially be used as an early biomarker of AD diagnosis.

Association between mild traumatic brain injury, brain structure, and mental health outcomes in the Adolescent Brain Cognitive Development Study.

BACKGROUND: Children that experience a mild traumatic brain injury (mTBI) are at an increased risk of neural alterations that can deteriorate mental health. We test the hypothesis that mTBI is associated with psychopathology and that structural brain metrics (e.g., volume, area) meaningfully mediate the relation in an adolescent population. METHODS: We analyzed behavioral and brain MRI data from 11,876 children who participated in the Adolescent Brain Cognitive Development (ABCD) Study. Mixed-effects models were used to examine the longitudinal association between mTBI and mental health outcomes. Bayesian methods were used to investigate brain regions that are intermediate between mTBI and symptoms of poor mental health. RESULTS: There were 199 children with mTBI and 527 with possible mTBI across the three ABCD Study visits. There was a 7% (IRR = 1.07, 95% CI: 1.01, 1.13) and 15% (IRR = 1.16, 95% CI: 1.05, 1.26) increased risk of emotional or behavioral problems in children that experienced possible mTBI or mTBI, respectively. Possible mTBI was associated with a 17% (IRR: 1.17, 95% CI: 0.99, 1.40) increased risk of experiencing distress following a psychotic-like experience. We did not find any brain regions that meaningfully mediated the relationship between mTBI and mental health outcomes. Analysis of volumetric measures found that approximately 2% to 5% of the total effect of mTBI on mental health outcomes operated through total cortical volume. Image intensity measure analyses determined that approximately 2% to 5% of the total effect was mediated through the left-hemisphere of the dorsolateral prefrontal cortex. CONCLUSION: Results indicate an increased risk of emotional and behavioral problems in children that experienced possible mTBI or mTBI. Mediation analyses did not elucidate the mechanisms underlying the association between mTBI and mental health outcomes.

Muscarinic M1, but not M4, receptor antagonism impairs divided attention in male rats.

Divided attention may be more important than ever to comprehend, given ubiquitous distractors in modern living. In humans, concern has been expressed about the negative impact of distraction in education, the home, and the workplace. While acetylcholine supports divided attention, in part via muscarinic receptors, little is known about the specific muscarinic subtypes that may contribute. We designed a novel, high-response rate test of auditory sustained attention, in which rats complete variable-ratio runs on one of two levers, rather than emitting a single response. By doing this, we can present a secondary visual distractor task during some trials, for which a correct nosepoke response is reinforced with a more palatable food pellet. The nonspecific muscarinic antagonist scopolamine impaired performance, and slowed and reduced lever press activity. We then explored antagonists that preferentially block the M1 and M4 subtypes, because these receptors are potential therapeutic targets for cognitive enhancers. Telenzepine, an M1-preferring antagonist, impaired divided attention performance, but not performance of the attention task without distraction. Telenzepine also had fewer nonspecific effects than scopolamine. In contrast, the M4-preferring antagonist tropicamide had no effects. Analysis of overall behavior also indicated that accuracy in the main attention task decreased as a function of engagement with the distractor task. These results implicate the M1 receptor in divided attention.

Biphasic effects of 5-HT1A agonism on impulsive responding are dissociable from effects on anxiety in the variable consecutive number task.

The serotonergic 5-HT1A receptor is known to be involved in both impulsivity and anxiety-related behavior. Although anxiety and impulsivity are different constructs, it has been shown that anxiogenesis can result in impulsiveness. It is therefore important to determine if the 5-HT1A receptor is involved in the commission of impulsive actions independent of its effects on anxiety. The 5-HT1A agonist 8-OH-DPAT (0.0125-0.1 mg/kg subcutaneous) increased impulsive action at low doses, but decreased it at higher doses, on the novel paced variable consecutive number with discriminative stimulus task (VCN). Neither the 5-HT1A antagonist WAY 100,635 (0.2-1.2 mg/kg subcutaneous), nor the noradrenergic antagonist and pharmacological stressor yohimbine (1-2 mg/kg intraperitoneal) altered measures of impulsivity. Stress induced by yohimbine was sufficient to produce anxiety-like behavior in the elevated zero maze, confirming that the VCN task is a selective assay of impulsive action that is not affected by anxiety. We hypothesize that the biphasic effect of 8-OH-DPAT is due to actions on presynaptic raphe 5-HT1A autoreceptors, and also postsynaptic 5-HT1A receptors. These results suggest that this receptor mediates impulsive action and that this is not secondary to its role in anxiety.