Systematic review of household transmission of Strep A: A potential site for prevention that has eluded attention.

BACKGROUND: Despite being the sixth most common infectious disease globally, transmission of Streptococcus pyogenes (Strep A) within the household remains an understudied driver of infection. We undertook a systematic review to better understand the transmission of Strep A between people within the home while highlighting opportunities for prevention. METHODS: A search strategy was applied to five databases between September 2022 and March 2023. Results were limited to those published between January 2000 and March 2023. Texts were reviewed by two authors and the following data extracted: article details (title, author, year), study type, transmission year, country, participant age/s, infection status, molecular testing, and transmission mode. Funding was provided by the Australian National Health and Medical Research Council (NHMRC, grant number GNT2010716). RESULTS: The final analysis comprised 28 texts. Only seven studies (25.0%) provided sufficient detail to identify the Strep A transmission mode. These were contact (4), vehicle (bedding; clothing; other fabric, and medical equipment, [2]), and contact with animals (1). All others were classified as household (specific mode unascertainable). Most articles reported outbreaks involving invasive Strep A infections. CONCLUSIONS: There is limited literature regarding household transmission of Strep A. Understanding transmission in this setting remains imperative to guide control methods.

Individual Patient Data Meta-Analysis of Dynamic Cerebral Autoregulation and Functional Outcome After Ischemic Stroke.

BACKGROUND: The relationship between dynamic cerebral autoregulation (dCA) and functional outcome after acute ischemic stroke (AIS) is unclear. Previous studies are limited by small sample sizes and heterogeneity. METHODS: We performed a 1-stage individual patient data meta-analysis to investigate associations between dCA and functional outcome after AIS. Participating centers were identified through a systematic search of the literature and direct invitation. We included centers with dCA data within 1 year of AIS in adults aged over 18 years, excluding intracerebral or subarachnoid hemorrhage. Data were obtained on phase, gain, coherence, and autoregulation index derived from transfer function analysis at low-frequency and very low-frequency bands. Cerebral blood velocity, arterial pressure, end-tidal carbon dioxide, heart rate, stroke severity and sub-type, and comorbidities were collected where available. Data were grouped into 4 time points after AIS: <24 hours, 24 to 72 hours, 4 to 7 days, and >3 months. The modified Rankin Scale assessed functional outcome at 3 months. Modified Rankin Scale was analyzed as both dichotomized (0 to 2 versus 3 to 6) and ordinal (modified Rankin Scale scores, 0-6) outcomes. Univariable and multivariable analyses were conducted to identify significant relationships between dCA parameters, comorbidities, and outcomes, for each time point using generalized linear (dichotomized outcome), or cumulative link (ordinal outcome) mixed models. The participating center was modeled as a random intercept to generate odds ratios with 95% CIs. RESULTS: The sample included 384 individuals (35% women) from 7 centers, aged 66.3±13.7 years, with predominantly nonlacunar stroke (n=348, 69%). In the affected hemisphere, higher phase at very low-frequency predicted better outcome (dichotomized modified Rankin Scale) at <24 (crude odds ratios, 2.17 [95% CI, 1.47-3.19]; P<0.001) hours, 24-72 (crude odds ratios, 1.95 [95% CI, 1.21-3.13]; P=0.006) hours, and phase at low-frequency predicted outcome at 3 (crude odds ratios, 3.03 [95% CI, 1.10-8.33]; P=0.032) months. These results remained after covariate adjustment. CONCLUSIONS: Greater transfer function analysis-derived phase was associated with improved functional outcome at 3 months after AIS. dCA parameters in the early phase of AIS may help to predict functional outcome.

Clinical compatibility of magnetic resonance imaging with magnetic intramedullary nails: a feasibility study.

INTRODUCTION: The use of magnetic resonance imaging (MRI) with a magnetic intramedullary lengthening nail in place is contraindicated per the manufacturer due to the concern of implant activation and migration. A prior in vitro study did not confirm these complications only noting that a 3.0 T MRI weakened the internal magnet. Therefore, a retrospective analysis of patients who underwent an MRI with a magnetic nail in place was performed to determine if any adverse effects occurred in the clinical setting. MATERIALS AND METHODS: A retrospective review of all patients who underwent an MRI with a magnetic lengthening nail in place was performed. The time spent being imaged in the MRI, number of times the patient entered the MRI suite, and the images obtained were recorded. Radiographs were performed before and after the MRI to determine if any hardware complications occurred. The patients were monitored for any adverse symptoms while they were in the suite. RESULTS: A total of 12 patients with 13 nails were identified. Two patients underwent imaging with a 3.0 T MRI while the remaining 10 underwent imaging with a 1.5 T MRI. Each patient entered the MRI suite 2.1 times and spent an average of 84.7 min being imaged in the MRI (range 21-494). No patients noted any adverse symptoms related to the nail while in the suite and no hardware complications were identified. CONCLUSION: MRI appears to be safe with a magnetic nail in place and did not result in any complications. Given the manufacturer's recommendations, informed consent should be obtained prior to an MRI being performed and a 3.0 T MRI should be avoided when possible if further activation of the nail is required.

Sex differences in risk-based decision-making and the modulation of risk preference by dopamine-2 like receptors in rats.

Heightened risk-based decision-making is observed across several neuropsychiatric disorders including schizophrenia, bipolar disorder, and Parkinson's disease, yet no treatments exist that effectively normalize this aberrant behavior. Preclinical risk-based decision-making paradigms have identified the important modulatory roles of dopamine and sex in the performance of such tasks, though specific task parameters may alter such effects (e.g., punishment and reward values). Previous work has highlighted the role of dopamine 2-like receptors (D2R) during performance of the Risk Preference Task (RPT) in male rats, however sex was not considered as a factor in this study, nor were treatments identified that reduced risk preference. Here, we utilized the RPT to determine sex-dependent differences in baseline performance and impact of the D2R receptor agonist pramipexole (PPX), and antagonist sulpiride (SUL) on behavioral performance. Female rats exhibited heightened risk-preference during baseline testing. Consistent with human studies, PPX increased risk-preference across sex, though the effects of PPX were more pronounced in female animals. Importantly, SUL reduced risk-preference in these rats across sexes. Thus, under the task specifications of the RPT that does not include punishment, female rats were more risk-preferring and required higher PPX doses to promote risky choices compared to males. Furthermore, blockade of D2R receptors may reduce risk-preference of rats, though further studies are required.

Automated abdominal adipose tissue segmentation and volume quantification on longitudinal MRI using 3D convolutional neural networks with multi-contrast inputs.

OBJECTIVE: Increased subcutaneous and visceral adipose tissue (SAT/VAT) volume is associated with risk for cardiometabolic diseases. This work aimed to develop and evaluate automated abdominal SAT/VAT segmentation on longitudinal MRI in adults with overweight/obesity using attention-based competitive dense (ACD) 3D U-Net and 3D nnU-Net with full field-of-view volumetric multi-contrast inputs. MATERIALS AND METHODS: 920 adults with overweight/obesity were scanned twice at multiple 3 T MRI scanners and institutions. The first scan was divided into training/validation/testing sets (n = 646/92/182). The second scan from the subjects in the testing set was used to evaluate the generalizability for longitudinal analysis. Segmentation performance was assessed by measuring Dice scores (DICE-SAT, DICE-VAT), false negatives (FN), and false positives (FP). Volume agreement was assessed using the intraclass correlation coefficient (ICC). RESULTS: ACD 3D U-Net achieved rapid (< 4.8 s/subject) segmentation with high DICE-SAT (median ≥ 0.994) and DICE-VAT (median ≥ 0.976), small FN (median ≤ 0.7%), and FP (median ≤ 1.1%). 3D nnU-Net yielded rapid (< 2.5 s/subject) segmentation with similar DICE-SAT (median ≥ 0.992), DICE-VAT (median ≥ 0.979), FN (median ≤ 1.1%) and FP (median ≤ 1.2%). Both models yielded excellent agreement in SAT/VAT volume versus reference measurements (ICC > 0.997) in longitudinal analysis. DISCUSSION: ACD 3D U-Net and 3D nnU-Net can be automated tools to quantify abdominal SAT/VAT volume rapidly, accurately, and longitudinally in adults with overweight/obesity.

Postnatal Phencyclidine-Induced Deficits in Decision Making Are Ameliorated by Optogenetic Inhibition of Ventromedial Orbitofrontal Cortical Glutamate Neurons.

Background: The orbitofrontal cortex (OFC) is essential for decision making, and functional disruptions within the OFC are evident in schizophrenia. Postnatal phencyclidine (PCP) administration in rats is a neurodevelopmental manipulation that induces schizophrenia-relevant cognitive impairments. We aimed to determine whether manipulating OFC glutamate cell activity could ameliorate postnatal PCP-induced deficits in decision making. Methods: Male and female Wistar rats (n = 110) were administered saline or PCP on postnatal days 7, 9, and 11. In adulthood, we expressed YFP (yellow fluorescent protein) (control), ChR2 (channelrhodopsin-2) (activation), or eNpHR 3.0 (enhanced halorhodopsin) (inhibition) in glutamate neurons within the ventromedial OFC (vmOFC). Rats were tested on the probabilistic reversal learning task once daily for 20 days while we manipulated the activity of vmOFC glutamate cells. Behavioral performance was analyzed using a Q-learning computational model of reinforcement learning. Results: Compared with saline-treated rats expressing YFP, PCP-treated rats expressing YFP completed fewer reversals, made fewer win-stay responses, and had lower learning rates. We induced similar performance impairments in saline-treated rats by activating vmOFC glutamate cells (ChR2). Strikingly, PCP-induced performance deficits were ameliorated when the activity of vmOFC glutamate cells was inhibited (halorhodopsin). Conclusions: Postnatal PCP-induced deficits in decision making are associated with hyperactivity of vmOFC glutamate cells. Thus, normalizing vmOFC activity may represent a potential therapeutic target for decision-making deficits in patients with schizophrenia.

Age-related dysregulation of homeostatic control in neuronal microcircuits.

Neuronal homeostasis prevents hyperactivity and hypoactivity. Age-related hyperactivity suggests homeostasis may be dysregulated in later life. However, plasticity mechanisms preventing age-related hyperactivity and their efficacy in later life are unclear. We identify the adult cortical plasticity response to elevated activity driven by sensory overstimulation, then test how plasticity changes with age. We use in vivo two-photon imaging of calcium-mediated cellular/synaptic activity, electrophysiology and c-Fos-activity tagging to show control of neuronal activity is dysregulated in the visual cortex in late adulthood. Specifically, in young adult cortex, mGluR5-dependent population-wide excitatory synaptic weakening and inhibitory synaptogenesis reduce cortical activity following overstimulation. In later life, these mechanisms are downregulated, so that overstimulation results in synaptic strengthening and elevated activity. We also find overstimulation disrupts cognition in older but not younger animals. We propose that specific plasticity mechanisms fail in later life dysregulating neuronal microcircuit homeostasis and that the age-related response to overstimulation can impact cognitive performance.

Omega-3 Fatty Acids, Cognition, and Brain Volume in Older Adults.

The elderly population is growing at increased rates and is expected to double in size by 2050 in the United States and worldwide. The consumption of healthy foods and enriched diets have been associated with improved cognition and brain health. The key nutrients common to many healthy foods and diets are the omega-3 polyunsaturated fatty acids (omega-3 FAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We explored whether omega-3 FA levels are associated with brain volume and cognition. Forty healthy, cognitively normal, Seventh-day Adventist older adults (mean age 76.3 years at MRI scan, 22 females) completed neurocognitive testing, a blood draw, and structural neuroimaging from 2016 to 2018. EPA and an overall omega-3 index were associated with individual measures of delayed recall (RAVLT-DR) and processing speed (Stroop Color) as well as entorhinal cortex thickness. EPA, DHA, and the omega-3 index were significantly correlated with the total white matter volume. The entorhinal cortex, frontal pole, and total white matter were associated with higher scores on delayed memory recall. This exploratory study found that among healthy, cognitively older adults, increased levels of omega-3 FAs are associated with better memory, processing speed, and structural brain measures.

Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models.

Neuronal hyperactivity is a key feature of early stages of Alzheimer's disease (AD). Genetic studies in AD support that microglia act as potential cellular drivers of disease risk, but the molecular determinants of microglia-synapse engulfment associated with neuronal hyperactivity in AD are unclear. Here, using super-resolution microscopy, 3D-live imaging of co-cultures, and in vivo imaging of lipids in genetic models, we found that spines become hyperactive upon Aß oligomer stimulation and externalize phosphatidylserine (ePtdSer), a canonical "eat-me" signal. These apoptotic-like spines are targeted by microglia for engulfment via TREM2 leading to amelioration of Aß oligomer-induced synaptic hyperactivity. We also show the in vivo relevance of ePtdSer-TREM2 signaling in microglia-synapse engulfment in the hAPP NL-F knock-in mouse model of AD. Higher levels of apoptotic-like synapses in mice as well as humans that carry TREM2 loss-of-function variants were also observed. Our work supports that microglia remove hyperactive ePtdSer+ synapses in Aß-relevant context and suggest a potential beneficial role for microglia in the earliest stages of AD.

Cortical networks for recognition of speech with simultaneous talkers.

The relative contributions of superior temporal vs. inferior frontal and parietal networks to recognition of speech in a background of competing speech remain unclear, although the contributions themselves are well established. Here, we use fMRI with spectrotemporal modulation transfer function (ST-MTF) modeling to examine the speech information represented in temporal vs. frontoparietal networks for two speech recognition tasks with and without a competing talker. Specifically, 31 listeners completed two versions of a three-alternative forced choice competing speech task: "Unison" and "Competing", in which a female (target) and a male (competing) talker uttered identical or different phrases, respectively. Spectrotemporal modulation filtering (i.e., acoustic distortion) was applied to the two-talker mixtures and ST-MTF models were generated to predict brain activation from differences in spectrotemporal-modulation distortion on each trial. Three cortical networks were identified based on differential patterns of ST-MTF predictions and the resultant ST-MTF weights across conditions (Unison, Competing): a bilateral superior temporal (S-T) network, a frontoparietal (F-P) network, and a network distributed across cortical midline regions and the angular gyrus (M-AG). The S-T network and the M-AG network responded primarily to spectrotemporal cues associated with speech intelligibility, regardless of condition, but the S-T network responded to a greater range of temporal modulations suggesting a more acoustically driven response. The F-P network responded to the absence of intelligibility-related cues in both conditions, but also to the absence (presence) of target-talker (competing-talker) vocal pitch in the Competing condition, suggesting a generalized response to signal degradation. Task performance was best predicted by activation in the S-T and F-P networks, but in opposite directions (S-T: more activation = better performance; F-P: vice versa). Moreover, S-T network predictions were entirely ST-MTF mediated while F-P network predictions were ST-MTF mediated only in the Unison condition, suggesting an influence from non-acoustic sources (e.g., informational masking) in the Competing condition. Activation in the M-AG network was weakly positively correlated with performance and this relation was entirely superseded by those in the S-T and F-P networks. Regarding contributions to speech recognition, we conclude: (a) superior temporal regions play a bottom-up, perceptual role that is not qualitatively dependent on the presence of competing speech; (b) frontoparietal regions play a top-down role that is modulated by competing speech and scales with listening effort; and (c) performance ultimately relies on dynamic interactions between these networks, with ancillary contributions from networks not involved in speech processing per se (e.g., the M-AG network).

Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases.

Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.

CADM2 is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice.

Impulsivity is a multidimensional heritable phenotype that broadly refers to the tendency to act prematurely and is associated with multiple forms of psychopathology, including substance use disorders. We performed genome-wide association studies (GWAS) of eight impulsive personality traits from the Barratt Impulsiveness Scale and the short UPPS-P Impulsive Personality Scale (N = 123,509-133,517 23andMe research participants of European ancestry), and a measure of Drug Experimentation (N = 130,684). Because these GWAS implicated the gene CADM2, we next performed single-SNP phenome-wide studies (PheWAS) of several of the implicated variants in CADM2 in a multi-ancestral 23andMe cohort (N = 3,229,317, European; N = 579,623, Latin American; N = 199,663, African American). Finally, we produced Cadm2 mutant mice and used them to perform a Mouse-PheWAS ("MouseWAS") by testing them with a battery of relevant behavioral tasks. In humans, impulsive personality traits showed modest chip-heritability (~6-11%), and moderate genetic correlations (rg = 0.20-0.50) with other personality traits, and various psychiatric and medical traits. We identified significant associations proximal to genes such as TCF4 and PTPRF, and also identified nominal associations proximal to DRD2 and CRHR1. PheWAS for CADM2 variants identified associations with 378 traits in European participants, and 47 traits in Latin American participants, replicating associations with risky behaviors, cognition and BMI, and revealing novel associations including allergies, anxiety, irritable bowel syndrome, and migraine. Our MouseWAS recapitulated some of the associations found in humans, including impulsivity, cognition, and BMI. Our results further delineate the role of CADM2 in impulsivity and numerous other psychiatric and somatic traits across ancestries and species.

Correlation of spinal epidural fat volume with body mass index: a longitudinal study.

PURPOSE: Spinal epidural lipomatosis is abnormal accumulation of normal fat in the epidural space with weight loss suggested as first-line therapy in select symptomatic patients. However, moderate to large longitudinal studies establishing concordant changes between body mass index and epidural fat are lacking. The purpose of this study was to longitudinally assess this relationship. METHODS: We performed an ancillary study of the Habitual Diet and Avocado Trial. Baseline and six-month abdominal MRIs were analyzed for 98 overweight or obese but otherwise healthy subjects. Dorsal epidural fat volumes in the lumbar spine were measured and correlated with changes in body mass index, changes in visceral fat volume, and demographic information. RESULTS: There was a linear relationship between body mass index changes and epidural fat volume changes with a one-point change in body mass index corresponding to a 45 mm3 change in dorsal epidural fat volume (p < 0.001, 95% CI 31.87 to 76.77) as well as between visceral fat volume changes and epidural fat volume changes (regression coefficient 0.51, p < 0.001, 95% CI 0.22 to 0.47). Age was inversely related with subjects older than 45.7 years tending to lose epidural fat (regression coefficient -0.22, p = 0.025, 95% CI -10.43 to -0.72). CONCLUSION: Changes in spinal dorsal epidural fat volume parallel changes in body mass index and visceral fat, supporting weight loss as initial treatment for uncomplicated obesity-associated spinal epidural lipomatosis.

Short-active gestational photoperiod reduces effortful choice behavior in mice, partial normalization by d-amphetamine.

RATIONALE: Seasonal birth patterns consistently implicate winter gestation as a risk factor for several psychiatric conditions. We recently demonstrated that short-active (SA; 19:5 light:dark)-i.e., "winter-like"-photoperiod exposure across gestation and early life (E0-P28) induces psychiatrically relevant behavioral abnormalities in adult mice, including reduced immobility in the forced swim test (FST) and effortful amotivation. It is unknown, however, whether these effects were driven primarily by prenatal or postnatal mechanisms, and whether perinatal SA photoperiod would similarly reduce effort expenditure in a task relevant to everyday decision-making. OBJECTIVES AND METHODS: We first tested male and female mice exposed to either gestational (E0-P0) or postnatal (E0-P28) SA photoperiod in the FST to determine whether the previously observed alteration was driven primarily by prenatal versus postnatal photoperiod. We then assessed whether SA gestational photoperiod reduces effortful choice behavior in the cross-species effort-based decision-making task (EBDMT) and whether any such deficit could be remediated by d-amphetamine (0.1 and 0.3 mg/kg, i.p.). RESULTS: Mice exposed to prenatal, but not postnatal, SA photoperiod exhibited reduced FST immobility relative to controls and also demonstrated condition-dependently reduced preference for high-effort/high-reward versus low-effort/low-reward contingencies in the EBDMT. This effortful choice deficit was normalized by 0.1 mg/kg amphetamine. CONCLUSIONS: These data: (1) suggest a greater contribution of gestational versus postnatal light conditions to the behavioral effects of perinatal SA photoperiod; and (2) implicate altered dopamine signaling in the behavioral phenotype of the SA-born mouse and possibly in the etiology of winter gestation-associated cases of psychiatric disease.

Reinforcement learning deficits exhibited by postnatal PCP-treated rats enable deep neural network classification.

The ability to appropriately update the value of a given action is a critical component of flexible decision making. Several psychiatric disorders, including schizophrenia, are associated with impairments in flexible decision making that can be evaluated using the probabilistic reversal learning (PRL) task. The PRL task has been reverse-translated for use in rodents. Disrupting glutamate neurotransmission during early postnatal neurodevelopment in rodents has induced behavioral, cognitive, and neuropathophysiological abnormalities relevant to schizophrenia. Here, we tested the hypothesis that using the NMDA receptor antagonist phencyclidine (PCP) to disrupt postnatal glutamatergic transmission in rats would lead to impaired decision making in the PRL. Consistent with this hypothesis, compared to controls the postnatal PCP-treated rats completed fewer reversals and exhibited disruptions in reward and punishment sensitivity (i.e., win-stay and lose-shift responding, respectively). Moreover, computational analysis of behavior revealed that postnatal PCP-treatment resulted in a pronounced impairment in the learning rate throughout PRL testing. Finally, a deep neural network (DNN) trained on the rodent behavior could accurately predict the treatment group of subjects. These data demonstrate that disrupting early postnatal glutamatergic neurotransmission impairs flexible decision making and provides evidence that DNNs can be trained on behavioral datasets to accurately predict the treatment group of new subjects, highlighting the potential for DNNs to aid in the diagnosis of schizophrenia.

Modulation of ventromedial orbitofrontal cortical glutamatergic activity affects the explore-exploit balance and influences value-based decision-making.

The balance between exploration and exploitation is essential for decision-making. The present study investigated the role of ventromedial orbitofrontal cortex (vmOFC) glutamate neurons in mediating value-based decision-making by first using optogenetics to manipulate vmOFC glutamate activity in rats during a probabilistic reversal learning (PRL) task. Rats that received vmOFC activation during informative feedback completed fewer reversals and exhibited reduced reward sensitivity relative to rats. Analysis with a Q-learning computational model revealed that increased vmOFC activity did not affect the learning rate but instead promoted maladaptive exploration. By contrast, vmOFC inhibition increased the number of completed reversals and increased exploitative behavior. In a separate group of animals, calcium activity of vmOFC glutamate neurons was recorded using fiber photometry. Complementing our results above, we found that suppression of vmOFC activity during the latter part of rewarded trials was associated with improved PRL performance, greater win-stay responding and selecting the correct choice on the next trial. These data demonstrate that excessive vmOFC activity during reward feedback disrupted value-based decision-making by increasing the maladaptive exploration of lower-valued options. Our findings support the premise that pharmacological interventions that normalize aberrant vmOFC glutamate activity during reward feedback processing may attenuate deficits in value-based decision-making.

Pinpointing the locus of GABAergic vulnerability in Alzheimer's disease.

The early stages of Alzheimer's disease (AD) have been linked to microcircuit dysfunction and pathophysiological neuronal firing in several brain regions. Inhibitory GABAergic microcircuitry is a critical feature of stable neural-circuit function in the healthy brain, and its dysregulation has therefore been proposed as contributing to AD-related pathophysiology. However, exactly how the critical balance between excitatory and inhibitory microcircuitry is modified by AD pathogenesis remains unclear. Here, we set the current evidence implicating dysfunctional GABAergic microcircuitry as a driver of early AD pathophysiology in a simple conceptual framework. Our framework is based on a generalised reductionist model of firing-rate control by local feedback inhibition. We use this framework to consider multiple loci that may be vulnerable to disruption by AD pathogenesis. We first start with evidence investigating how AD-related processes may impact the gross number of inhibitory neurons in the network. We then move to discuss how pathology may impact intrinsic cellular properties and firing thresholds of GABAergic neurons. Finally, we cover how AD-related pathogenesis may disrupt synaptic connectivity between excitatory and inhibitory neurons. We use the feedback inhibition framework to discuss and organise the available evidence from both preclinical rodent work and human studies in AD patients and conclude by identifying key questions and understudied areas for future investigation.

Homeostatic regulation through strengthening of neuronal network-correlated synaptic inputs.

Homeostatic regulation is essential for stable neuronal function. Several synaptic mechanisms of homeostatic plasticity have been described, but the functional properties of synapses involved in homeostasis are unknown. We used longitudinal two-photon functional imaging of dendritic spine calcium signals in visual and retrosplenial cortices of awake adult mice to quantify the sensory deprivation-induced changes in the responses of functionally identified spines. We found that spines whose activity selectively correlated with intrinsic network activity underwent tumor necrosis factor alpha (TNF-α)-dependent homeostatic increases in their response amplitudes, but spines identified as responsive to sensory stimulation did not. We observed an increase in the global sensory-evoked responses following sensory deprivation, despite the fact that the identified sensory inputs did not strengthen. Instead, global sensory-evoked responses correlated with the strength of network-correlated inputs. Our results suggest that homeostatic regulation of global responses is mediated through changes to intrinsic network-correlated inputs rather than changes to identified sensory inputs thought to drive sensory processing.