Exploring Preclinical Medical Students' Experience Facilitating Group Dialectical Behavior Therapy (DBT) for a Student-Run Mental Health Clinic: A Qualitative Study.

OBJECTIVE: This report explores the experiences of preclinical medical students who led group dialectical behavior therapy (DBT) for a student-run LGBTQ + mental health clinic. METHODS: In the clinic, experienced clinicians trained and supervised preclinical medical students to facilitate DBT groups. The authors conducted a qualitative study to understand the impact of the DBT groups on the student facilitators via semi-structured interviews, which were evaluated using thematic analysis. RESULTS: The clinic hosted nine iterations of group DBT facilitated by preclinical medical students, involving 18 student leaders and 30 patients. Twelve student facilitators were interviewed. Participants had a diverse array of specialty interests and were primarily motivated by the opportunity for early clinical experience. They reported improved clinical skills, increased appreciation of psychotherapy as a treatment modality, and increased interest in incorporating psychotherapy in their future practice. Furthermore, participants reported using DBT skills to cultivate wellbeing during clerkship year and in their personal lives. CONCLUSIONS: Offering preclinical medical students the opportunity to lead group DBT therapy is a novel educational model providing early training in psychotherapy techniques. This opportunity for early direct patient experience in a supervised group setting attracted medical students with a diverse range of specialty interests. This model provided medical students specific DBT skills to implement in future patient care interactions and to maintain their personal wellbeing throughout medical training. The broad appeal and lasting effects of this program may prove beneficial at other institutions.

Weill Cornell Medicine Wellness Qlinic: Adapting the Student-Run Clinic Model to Expand Mental Health Services and Medical Education.

The Weill Cornell Medicine Wellness Qlinic (Wellness Qlinic) is a student-run mental health clinic serving the lesbian, gay, bisexual, transgender, and queer (LGBTQ +) community in New York City. Student-run clinics have successfully provided primary care to underserved communities experiencing barriers to accessing health care. Psychiatric evaluation and medication management have also been implemented in several student-run clinics, but providing sustainable psychotherapy services has been a challenge. In this paper, we present a student-run mental health program incorporating interdisciplinary trainees to provide robust short-term psychiatric treatment, including individual psychotherapy, medication management, and group therapy. Results of a chart-review study to evaluate patient engagement and treatment outcomes are presented. The Wellness Qlinic's treatment model resulted in 90% patient retention and positive clinical outcomes for patients while addressing an education and training gap in LGBTQ + mental health for multidisciplinary mental health care providers.

Hippocampal astrocytes induce sex-dimorphic effects on memory.

Astrocytic receptors influence cognitive function and can promote behavioral deficits in disease. These effects may vary based on variables such as biological sex, but it is not known if the effects of astrocytic receptors are dependent on sex. We leveraged in vivo gene editing and chemogenetics to examine the roles of astrocytic receptors in spatial memory and other processes. We show that reductions in metabotropic glutamate receptor 3 (mGluR3), the main astrocytic glutamate receptor in adults, impair memory in females but enhance memory in males. Similarly, increases in astrocytic mGluR3 levels have sex-dependent effects and enhance memory in females. mGluR3 manipulations also alter spatial search strategies during recall in a sex-specific manner. In addition, acute chemogenetic stimulation of Gi/o-coupled or Gs-coupled receptors in hippocampal astrocytes induces bidirectional and sex-dimorphic effects on memory. Thus, astrocytes are sex-dependent modulators of cognitive function and may promote sex differences in aging and disease.

Astrocytic TDP-43 dysregulation impairs memory by modulating antiviral pathways and interferon-inducible chemokines.

Transactivating response region DNA binding protein 43 (TDP-43) pathology is prevalent in dementia, but the cell type-specific effects of TDP-43 pathology are not clear, and therapeutic strategies to alleviate TDP-43-linked cognitive decline are lacking. We found that patients with Alzheimer's disease or frontotemporal dementia have aberrant TDP-43 accumulation in hippocampal astrocytes. In mouse models, induction of widespread or hippocampus-targeted accumulation in astrocytic TDP-43 caused progressive memory loss and localized changes in antiviral gene expression. These changes were cell-autonomous and correlated with impaired astrocytic defense against infectious viruses. Among the changes, astrocytes had elevated levels of interferon-inducible chemokines, and neurons had elevated levels of the corresponding chemokine receptor CXCR3 in presynaptic terminals. CXCR3 stimulation altered presynaptic function and promoted neuronal hyperexcitability, akin to the effects of astrocytic TDP-43 dysregulation, and blockade of CXCR3 reduced this activity. Ablation of CXCR3 also prevented TDP-43-linked memory loss. Thus, astrocytic TDP-43 dysfunction contributes to cognitive impairment through aberrant chemokine-mediated astrocytic-neuronal interactions.

Shared effects of DISC1 disruption and elevated WNT signaling in human cerebral organoids.

The development of three-dimensional culture methods has allowed for the study of developing cortical morphology in human cells. This provides a new tool to study the neurodevelopmental consequences of disease-associated mutations. Here, we study the effects of isogenic DISC1 mutation in cerebral organoids. DISC1 has been implicated in psychiatric disease based on genetic studies, including its interruption by a balanced translocation that increases the risk of major mental illness. Isogenic wild-type and DISC1-disrupted human-induced pluripotent stem cells were used to generate cerebral organoids, which were then examined for morphology and gene expression. We show that DISC1-mutant cerebral organoids display disorganized structural morphology and impaired proliferation, which is phenocopied by WNT agonism and rescued by WNT antagonism. Furthermore, there are many shared changes in gene expression with DISC1 disruption and WNT agonism, including in neural progenitor and cell fate markers, regulators of neuronal migration, and interneuron markers. These shared gene expression changes suggest mechanisms for the observed morphologic dysregulation with DISC1 disruption and points to new avenues for future studies. The shared changes in three-dimensional cerebral organoid morphology and gene expression with DISC1 interruption and WNT agonism further strengthens the link between DISC1 mutation, abnormalities in WNT signaling, and neuropsychiatric disease.

Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability.

Alzheimer's disease (AD) induces memory and cognitive impairment in the absence of motor and sensory deficits during its early and middle course. A major unresolved question is the basis for this selective neuronal vulnerability. Aß, which plays a central role in AD pathogenesis, is generated throughout the brain, yet some regions outside of the limbic and cerebral cortices are relatively spared from Aß plaque deposition and synapse loss. Here, we examine neurons derived from iPSCs of patients harboring an amyloid precursor protein mutation to quantify AD-relevant phenotypes following directed differentiation to rostral fates of the brain (vulnerable) and caudal fates (relatively spared) in AD. We find that both the generation of Aß and the responsiveness of TAU to Aß are affected by neuronal cell type, with rostral neurons being more sensitive than caudal neurons. Thus, cell-autonomous factors may in part dictate the pattern of selective regional vulnerability in human neurons in AD.

Ephrins and Ephs in cochlear innervation and implications for advancing cochlear implant function.

OBJECTIVES/HYPOTHESIS: Determine if the neuronal pathfinding cues resulting from Eph/ephrin interaction in the inner ear play a role in establishing the tonotopic innervation of the cochlea. STUDY DESIGN: Protein expression of Ephs and ephrins was evaluated in the inner ear of mice and chicks. Subsequently, in vitro, in vivo, and functional electrophysiologic studies were performed to indicate that Ephs and ephrins play a role regulating the normal innervation patterns in the mouse inner ear. METHODS: Eph and ephrin protein expression was identified in the inner ear by western blotting and localized by fluorescence immunohistochemistry and X-gal staining. Eph/ephrin effects on neurite outgrowth was assessed via co-culture with EphB2 expressing COS-1 cells. Anatomic effects of disrupting Eph/ephrin signaling on cochlear innervation were determined with lipophilic dye tracing and functional effects with auditory brainstem response (ABR). RESULTS: Expression of several different Ephs and ephrins were found in the inner ear of chicks and mice. The changes in ephrin-A2 immunoreactivity after gentamicin ototoxicity coincide with the spatio-temporal pattern of hair cell loss and regeneration in the chick cochlea. EphB2 inhibited outgrowth of spiral ganglion cell neurites. Knockout mice with null function of EphB1, EphB2, and EphB3 demonstrated abnormal inner ear innervation and elevated ABR thresholds, indicating hearing loss. CONCLUSIONS: Ephrin-A2 may be involved in the guidance of ganglion cells to hair cells in the chick. Disruption of Eph/ephrin signaling results in abnormal innervation and hearing loss, suggesting that these proteins play a role in establishing normal innervation patterns in the mouse cochlea. LEVEL OF EVIDENCE: NA

Identifying Distal cis-acting Gene-Regulatory Sequences by Expressing BACs Functionalized with loxP-Tn10 Transposons in Zebrafish.

Bacterial Artificial Chromosomes (BACs) are large pieces of DNA from the chromosomes of organisms propagated faithfully in bacteria as large extra-chromosomal plasmids. Expression of genes contained in BACs can be monitored after functionalizing the BAC DNA with reporter genes and other sequences that allow stable maintenance and propagation of the DNA in the new host organism. The DNA in BACs can be altered within its bacterial host in several ways. Here we discuss one such approach, using Tn10 mini-transposons, to introduce exogenous sequences into BACs for a variety of purposes. The largely random insertions of Tn10 transposons carrying lox sites have been used to position mammalian cell-selectable antibiotic resistance genes, enhancer-traps and inverted repeat ends of the vertebrate transposon Tol2 precisely at the ends of the genomic DNA insert in BACs. These modified BACs are suitable for expression in zebrafish or mouse, and have been used to functionally identify important long-range gene regulatory sequences in both species. Enhancer-trapping using BACs should prove uniquely useful in analyzing multiple discontinuous DNA domains that act in concert to regulate expression of a gene, and is not limited by genome accessibility issues of traditional enhancer-trapping methods.

Disruption of ephrin B/Eph B interaction results in abnormal cochlear innervation patterns.

OBJECTIVE: To determine the expression patterns of B ephrins and Ephs in the cochlea and identify functional consequences of disruption of ephrin B/Eph B interactions in both cultured spiral ganglion neurons and in the cochlea of live animals. STUDY DESIGN: The expression patterns of various B ephrins and Ephs were determined in mice with Lac-Z mutation. Mice with null function of individual B ephrin and Eph proteins and those with multiple knockouts were studied for cochlear innervation patterns. METHODS: Mice with B ephrins and Ephs disrupted with the ß-galactosidase gene were sacrificed at P6, and their cochleae isolated and processed for Lac-Z staining to determine expression of these proteins in cochlear tissue. Spiral ganglion cells from wild-type as well as ephrin B1 knockout mice were isolated and cocultured with Eph B2 expressing Cos1 cells and neurite lengths were determined. Fluorescent lipophillic dyes were used to label spiral ganglion cell nerve fibers to determine cochlear innervation patterns in wild-type and knockout mice. RESULTS: Eph B1, B2, and ephrin B2 but not B3 was expressed in the cochlea. Eph B2 inhibited outgrowth of spiral ganglion cell axons from wild-type mice, but not from ephrin B1 knockout mice in culture. Knockout mice with null function of ephrin B1 alone or Eph B1, Eph B2, Eph B3 in combination demonstrated abnormal innervation patterns in the organ of Corti. CONCLUSIONS: Disruption of B ephrins and Ephs results in functional consequences in spiral ganglion cells, suggesting that these proteins play a role in establishing normal innervation patterns in the cochlea.