Faculty Bibliography

The piriform cortex (PCx), commonly considered to be the primary olfactory sensory cortex, differs from other mammalian sensory cortices by not displaying a stimulus-specific spatial organization but rather displaying widely distributed odor-evoked activity. However, there is evidence of a PCx spatial organization based on output neuron targeting. Here, we performed double-labeled retrograde tracing to reveal neuronal populations of PCx output neurons that project to two regions affiliated with different behavioral significance, the basolateral amygdala (BLA) and lateral orbitofrontal (LO) cortex networks. We found that PCx neurons projecting to BLA and LO are distinct in spatial distribution with minimal overlap, supporting the hypothesis that while odor input is distributed randomly across the PCx, PCx output neurons are organized into target-specific neuronal populations that potentially serve as functional units for odor encoding and odor-guided behavior.

INTRODUCTION/BACKGROUND:The long-standing cholinergic hypothesis posits that cholinergic signaling is uniformly deficient in Alzheimer's disease (AD) and Down syndrome (DS). We tested the hypothesis that this deficiency occurs primarily late in disease, while early stages involve excessive cholinergic signaling, with distinct implications for memory. METHODS:Tg2576 (AD model; n = 38), Ts65Dn (DS model; n = 14), and wild-type (WT; n = 17) mice at young (3 to 4 months) and old (>14 months) ages received treatments to reduce cholinergic signaling (medial septum chemogenetic inhibition, muscarinic antagonist scopolamine) or enhance it (acetylcholinesterase inhibitor donepezil). Memory assessments used novel object recognition. RESULTS:Anticholinergic manipulations restored memory in young Tg2576 and Ts65Dn mice but impaired age-matched WT mice. Conversely, donepezil improved the memory of old Tg2576, Ts65Dn, and WT but not young Tg2576 and Ts65Dn animals. DISCUSSION/CONCLUSIONS:These findings refine and challenge the cholinergic hypothesis, revealing for the first time a functional shift from cholinergic hyperactivity driving early cognitive impairment to late-stage degeneration requiring enhancement.

BackgroundRates of psychiatric disorders and related hospitalizations among youth in the United States have risen substantially over recent decades. Despite evidence supporting outpatient care, fewer than half of youth receive treatment. When outpatient management is insufficient, inpatient psychiatric hospitalization is required, though it is costly, disruptive, and limited in availability. Prior research on predictors of inpatient length of stay has been dated and heterogenous, highlighting the need to identify current clinical and non-clinical factors associated with prolonged stays among youth populations.MethodThis IRB-approved retrospective study reviewed the medical records of 1,101 child and adolescent patients admitted to an inpatient psychiatric unit between June 1, 2018, and November 30, 2021. Baseline sociodemographic and clinical data were collected, and LOS was categorized into three groups: below-average (0-6 days), average (7-14 days), and above-average (15+ days). Comparative statistics were performed, and linear regression was used to identify independent predictors of LOS.ResultsThe average LOS was 10.5 days. Significant predictors of prolonged LOS included public insurance, admission for psychosis or suicide attempt, involvement of child protective services, number of prior hospitalizations, and number of medications prior to admission.ConclusionProlonged LOS in psychiatrically hospitalized youth is associated with specific clinical and non-clinical factors. Identifying these predictors at admission can guide treatment planning and set realistic expectations for families. Further research is required to validate these findings and explore the impact of LOS on treatment outcomes.

Despite decades of neuroimaging research, how white matter develops along the length of major tracts in humans remains unknown. Here, we identify fundamental patterns of white matter maturation by examining developmental variation along major, long-range cortico-cortical tracts in youth ages 5-23 years using diffusion MRI from three large-scale, cross-sectional datasets (total N = 2716). Across datasets, we delineate two replicable axes of human white matter development. First, we find a deep-to-superficial axis, in which superficial tract regions near the cortical surface exhibit greater age-related change than deep tract regions. Second, we demonstrate that the development of superficial tract regions aligns with the cortical hierarchy defined by the sensorimotor-association axis, with tract ends adjacent to sensorimotor cortices maturing earlier than those adjacent to association cortices. These results reveal developmental variation along tracts that conventional tract-average analyses have previously obscured, challenging the implicit assumption that white matter tracts mature uniformly along their length. Such developmental variation along tracts may have functional implications, including mitigating ephaptic coupling in densely packed deep tract regions and tuning neural synchrony through hierarchical development in superficial tract regions - ultimately refining neural transmission in youth.

OBJECTIVE:To assess associations between exposure to intrauterine SARS-CoV-2 and subsequent child neurodevelopment in a large, diverse cohort with confirmation of maternal SARS-CoV-2 status. STUDY DESIGN/METHODS:edition (ASQ-3) and at 18 months with the ASQ Social-Emotional (ASQ-SE) and the Modified Checklist for Autism in Toddlers-Revised (M-CHAT-R). We compared exposed and unexposed infants' ASQ-3 total and subdomain scores, ASQ-SE and M-CHAT-R scores, and proportions meeting published referral thresholds, using multivariable linear and logistic regression. RESULTS:Among 1179 participants enrolled, 1008 (85.5%) had exposure, with 806 (80.0%) exposed during Omicron predominance. Of those with known timing, 349 (41.4%) and 295 (35.0%) were exposed in the second and third trimesters of pregnancy respectively. Exposure was not associated with differences in ASQ-3 (adjusted difference: -0.61, 95% CI: -10.03, 8.81) or ASQ-3 subdomains at 12 months, ASQ-SE at 18 months (adjusted difference: 0.19, 95% CI: -4.02, 4.41), or M-CHAT-R scores. Findings were similar for proportions meeting referral thresholds, and when stratified by variant or by trimester. CONCLUSIONS:In this multicenter cohort largely exposed since Omicron and in second or third trimester, intrauterine SARS-CoV-2 exposure was not associated with neurodevelopmental screening outcomes through 18 months of age. Further assessments of the impact of intrauterine SARS-CoV-2 on neurodevelopment beyond 18 months of age are needed.

BACKGROUND:Negative reactivity (NR) and behavioral inhibition (BI), temperamental traits characterized by novelty-evoked distress and avoidance respectively, represent risk markers for anxiety. However, not all infants with NR and BI develop anxiety. Pathways from infant temperament to anxiety remain underspecified. This study tests the hypothesis that heightened neural sensitivity to unexpected sensory stimuli in infancy moderates risk for anxiety. METHODS:Data from the Temperament Over Time Study (N=291) were utilized. Infants completed laboratory-based assessments of NR at 4 months (M) and BI at 2-3 years. BI was also assessed using parent-report. At 9 and 36M, electroencephalography was collected during a passive three-stimulus auditory oddball task, and the mismatch response (MMR) and novelty P3 were quantified. Adolescent anxiety was measured using parent- and self-reports, and clinical interviews at 13 and 15 years. Structural equational modeling analyses were applied to examine whether infants' MMR or novelty P3 at 9 and 36M modulate relations between NR, BI, and adolescent anxiety. RESULTS:The MMR at 9M moderated the relation between NR and BI, and the MMR at 36M moderated the relation between BI and 13-year anxiety. In both cases, a more negative MMR was associated with elevated risk. This association was not present for attention problems or externalizing outcomes. Additional exploratory analyses showed that the novelty P3 mediated pathways from NR to social anxiety. CONCLUSIONS:Individual differences in the infant's neural response to unexpected stimuli relate to temperamental risk for anxiety.

Pyramidal cells (PCs) of hippocampal area CA2 exhibit increased excitability in temporal lobe epilepsy (TLE) and in mouse models of TLE. In epileptic mice, selective inhibition of CA2 PCs reduces chronic seizures. Here we asked if activating CA2 PCs increases seizures. Mice expressing Cre recombinase in CA2 PCs (Amigo2-Cre mice) were injected with the convulsant pilocarpine to induce a period of severe seizures (status epilepticus, SE), which leads to chronic seizures after 3-4 weeks (epilepsy). Epileptic mice were injected with a Cre-dependent adeno-associated virus (AAV) to express an excitatory designer receptor exclusively activated by designer drug (eDREADD; hM3Dq) in dorsal CA2 bilaterally and implanted with subdural EEG electrodes. After recovery, mice were recorded continuously using video and EEG for 6 weeks, 3 weeks with drinking water containing the eDREADD activator clozapine-N-oxide (CNO) and 3 weeks without CNO. CA2 activation with CNO caused a significant increase in seizure frequency and duration. Seizures occurred in clusters (many seizures per day over several consecutive days) and mice given water with CNO had a greater maximum number of seizures per day during a cluster compared to water without CNO. CNO had no significant effect in control mice. In naïve Amigo2-Cre mice expressing hM3Dq, pre-treatment with CNO before pilocarpine administration shortened the latency to SE and increased EEG power at the start of SE. Taken together with prior findings, the results suggest that CA2 is a control point for regulating seizures in the pilocarpine mouse model of TLE.

STUDY QUESTION/OBJECTIVE:Is there an association between infertility diagnosis and long-term adult-onset psychiatric conditions in women? SUMMARY ANSWER/CONCLUSIONS:Infertility diagnosis in women is linked to higher risks of mood disorders, anxiety- and stress-related disorders, and behavioral syndromes with physical components, but not schizophrenia or other psychotic disorders, particularly notable from 9 years after the first infertility diagnosis. WHAT IS KNOWN ALREADY/BACKGROUND:Infertility, especially in women, is associated with major mental health challenges around the time of diagnosis. However, the long-term connection with a wide range of psychiatric disorders is largely unknown. STUDY DESIGN, SIZE, DURATION/METHODS:This study employed a matched-pair design within the UK Biobank (UKB) cohort, including 3893 females with a diagnosis of infertility and 15 603 matched female controls, totaling 19 496 participants. PARTICIPANTS/MATERIALS, SETTING, METHODS/METHODS:Female UKB participants with a diagnosis of infertility were matched to females without the diagnosis in a 1:4 ratio based on year of birth, index of deprivation of their residency area, and primary care data linkage status. The diagnosis of female infertility was identified by the first occurrence of a primary or secondary diagnosis in either primary care or hospital records. Additional analyses explored interactions between infertility diagnosis and both miscarriage and childbearing status on psychiatric conditions. MAIN RESULTS AND THE ROLE OF CHANCE/RESULTS:Diagnosis of infertility was associated with higher risks of mood disorders, anxiety- and stress-related disorders, and behavioral syndromes with physical components, but not with schizophrenia or other psychotic disorders. The most notable increases in the risk of psychiatric diagnoses were observed 9 years after the first infertility diagnosis. No significant interactions were found between infertility diagnosis and either miscarriage or childbearing status on psychiatric conditions. Sensitivity analysis confirmed the robustness of these associations across different data sources for infertility diagnosis and psychiatric condition ascertainment. LIMITATIONS, REASONS FOR CAUTION/CONCLUSIONS:The study's limitations include the racial homogeneity and the overall healthier status of the UKB cohort compared to the general UK population and the potential underestimation of associations due to misclassification of subfecund women. WIDER IMPLICATIONS OF THE FINDINGS/CONCLUSIONS:These results emphasize the need for integrated mental health support in infertility care and long-term monitoring of infertility patients for psychiatric risks. STUDY FUNDING/COMPETING INTEREST(S)/BACKGROUND:None. No competing interests were declared. TRIAL REGISTRATION NUMBER/BACKGROUND:n/a.