Sexual Dimorphism in the Closure of the Hippocampal Postnatal Critical Period of Synaptic Plasticity after Intrauterine Growth Restriction: Link to Oligodendrocyte and Glial Dysregulation.

Intrauterine growth restriction (IUGR) resulting from hypertensive disease of pregnancy (HDP) leads to sexually dimorphic hippocampal-dependent cognitive and memory impairment in humans. In our translationally relevant mouse model of IUGR incited by HDP, we have previously shown that the synaptic development in the dorsal hippocampus including GABAergic development, NPTX2+ excitatory synaptic formation, axonal myelination, and perineural net (PNN) formation were perturbed by IUGR at adolescent equivalence in humans (P40). The persistence of these disturbances through early adulthood and the potential upstream mechanisms are currently unknown. Thus, we hypothesized that NPTX2+ expression, PNN formation, axonal myelination, all events closing synaptic development in the hippocampus, will be persistently perturbed, particularly affecting IUGR female mice through P60 given the fact that they had worse short-term recognition memory in this model. We additionally hypothesized that such sexual dimorphism is linked to persistent glial dysregulation. We induced IUGR by a micro-osmotic pump infusion of a potent vasoconstrictor U-46619, a thromboxane A2-analog, in the last week of the C57BL/6 mouse gestation to precipitate HDP. Sham-operated mice were used as controls. At P60, we assessed hippocampal and hemispheric volumes, NPTX2 expression, PNN formation, as well as myelin basic protein (MBP), Olig2, APC/CC1, and M-NF expression. We also evaluated P60 astrocytic (GFAP) reactivity and microglial (Iba1 and TMEM119) activation using immunofluorescent-immunohistochemistry and Imaris morphological analysis plus cytokine profiling using Meso Scale Discovery platform. IUGR offspring continued to have smaller hippocampal volumes at P60 not related to changes in hemisphere volume. NPTX2+ puncta counts and volumes were decreased in IUGR hippocampal CA subregions of female mice compared to sex-matched shams. Intriguingly, NPTX2+ counts and volumes were concurrently increased in the dentate gyrus (DG) subregion. PNN volumes were smaller in CA1 and CA3 of IUGR female mice along with PNN intensity in CA3 but they had larger volumes in the CA3 of IUGR male mice. The myelinated axon (MBP+) areas, volumes, and lengths were all decreased in the CA1 of IUGR female mice compared to sex-matched shams, which correlated with a decrease in Olig2 nuclear expression. No decrease in the number of APC/CC1+ mature oligodendrocytes was identified. We noted an increase in M-NF expression in the mossy fibers connecting DG to CA3 only in IUGR female mice. Reactive astrocytes denoted by GFAP areas, volumes, lengths, and numbers of branching were increased in IUGR female CA1 but not in IUGR male CA3 compared to sex-matched shams. Lastly, activated microglia were only detected in IUGR female CA1 and CA3 subregions. We detected no difference in the cytokine profile between sham and IUGR adult mice of either sex. Collectively, our data support a sexually dimorphic impaired closure of postnatal critical period of synaptic plasticity in the hippocampus of young adult IUGR mice with greater effects on females. A potential mechanism supporting such dimorphism may include oligodendrocyte dysfunction in IUGR females limiting myelination, allowing axonal overgrowth followed by a reactive glial-mediated synaptic pruning.

Intrauterine Growth Restriction Disrupts the Postnatal Critical Period of Synaptic Plasticity in the Mouse Dorsal Hippocampus in a Model of Hypertensive Disease of Pregnancy.

INTRODUCTION: Intrauterine growth restriction (IUGR) from hypertensive disease of pregnancy complicates up to 10% of all pregnancies. Significant hippocampal-dependent cognitive and memory impairments as well as neuropsychiatric disorders have been linked to IUGR. Because disturbance of the hippocampal critical period (CPd) of synaptic plasticity leads to impairments similar to those described in IUGR human offspring, we hypothesized that IUGR would perturb the CPd of synaptic plasticity in the mouse hippocampus in our model. METHODS: IUGR was produced by a micro-osmotic pump infusion of the potent vasoconstrictor U-46619, a thromboxane A2-agonist, at embryonic day 12.5 in C57BL/6J mouse dams to precipitate hypertensive disease of pregnancy and IUGR. Sham-operated mice acted as controls. At P10, P18, and P40, we assessed astrogliosis using GFAP-IHC. In dorsal CA1 and CA3 subfields, we assessed the immunoreactivities (IR) (IF-IHC) to (i) parvalbumin (PV) and glutamate decarboxylase (GAD) 65/67, involved in CPd onset; (ii) PSA-NCAM that antagonizes CPd onset; (iii) NPTX2, necessary for excitatory synapse formation and engagement of CPd; and (iv) MBP and WFA, staining perineural nets (PNNs), marking CPd closure. ImageJ/Fiji and IMARIS were used for image processing and SPSS v24 for statistical analysis. RESULTS: Although PV+ interneuron numbers and IR intensity were unchanged, development of GAD65/67+ synaptic boutons was accelerated at P18 IUGR mice and inversely correlated with decreased expression of PSA-NCAM in the CA of P18 IUGR mice at P18. NPTX2+ puncta and total volume were persistently decreased in the CA3 pyramidal and radiatum layers of IUGR mice from P18 to P40. At P40, axonal myelination (MBP+) in CA3 of IUGR mice was decreased and correlated with NPTX2 deficits. Lastly, the volume and integrity of the PNNs in the dorsal CA was disrupted in IUGR mice at P40. DISCUSSION/CONCLUSION: IUGR disrupts the molecular and structural initiation, consolidation, and closure of the CPd of synaptic plasticity in the mouse hippocampus in our model, which may explain the learning and memory deficits observed in juvenile IUGR mice and the cognitive disorders seen in human IUGR offspring. The mechanistic links warrant further investigation, to identify therapeutic targets to prevent neurodevelopmental deficits in patients affected by IUGR.

Dysregulation of ErbB4 Signaling Pathway in the Dorsal Hippocampus after Neonatal Hypoxia-Ischemia and Late Deficits in PV+ Interneurons, Synaptic Plasticity and Working Memory.

Neonatal hypoxic-ischemic (HI) injury leads to deficits in hippocampal parvalbumin (PV)+ interneurons (INs) and working memory. Therapeutic hypothermia (TH) does not prevent these deficits. ErbB4 supports maturation and maintenance of PV+ IN. Thus, we hypothesized that neonatal HI leads to persistent deficits in PV+ INs, working memory and synaptic plasticity associated with ErbB4 dysregulation despite TH. P10 HI-injured mice were randomized to normothermia (NT, 36 °C) or TH (31 °C) for 4 h and compared to sham. Hippocampi were studied for α-fodrin, glial fibrillary acidic protein (GFAP), and neuroregulin (Nrg) 1 levels; erb-b2 receptor tyrosine kinase 4 (ErbB4)/ Ak strain transforming (Akt) activation; and PV, synaptotagmin (Syt) 2, vesicular-glutamate transporter (VGlut) 2, Nrg1, and ErbB4 expression in coronal sections. Extracellular field potentials and behavioral testing were performed. At P40, deficits in PV+ INs correlated with impaired memory and coincided with blunted long-term depression (LTD), heightened long-term potentiation (LTP) and increased Vglut2/Syt2 ratio, supporting excitatory-inhibitory (E/I) imbalance. Hippocampal Nrg1 levels were increased in the hippocampus 24 h after neonatal HI, delaying the decline documented in shams. Paradoxically ErbB4 activation decreased 24 h and again 30 days after HI. Neonatal HI leads to persistent deficits in hippocampal PV+ INs, memory, and synaptic plasticity. While acute decreased ErbB4 activation supports impaired maturation and survival after HI, late deficit reemergence may impair PV+ INs maintenance after HI.

Bariatric Surgery Is Highly Effective and Underutilized in Patients with ADHD: A 5-Year Retrospective Cohort Study.

INTRODUCTION: Obesity and ADHD have become increasingly common diagnoses. In the last decade, research has found that there is a high prevalence of obesity in patients with ADHD. The mainstays of management in the general population include lifestyle modifications, pharmacotherapies, and/or bariatric surgery. However, there is a lack of understanding of appropriate management of patients with both ADHD and obesity. METHODS: We identified those with obesity for at least five consecutive years (BMI > 30) in the TriNetX database before separating into two groups based on the presence or absence of ADHD. We assessed both the distribution of treatment modalities and the change in average BMI over time in each of our four groups across 5 years. RESULTS: Average BMI decreased over time in all groups, with the smallest change seen in the ADHD Pharmacology cohort (- 0.366 kg/m2) and the largest in the ADHD Surgery group (- 8.532 kg/m2). Average BMIs at the 5-year mark were significantly different. CONCLUSION: Our research found that pharmacological management of individuals with ADHD was only half as effective for individuals with ADHD than our control. Though surgical management of patients with ADHD is roughly 20 times more effective in managing obesity, it was not used as frequently in comparison to medication for management of weight.

PatientsLikeMe and Online Patient Support Communities in Dermatology.

Online patient-oriented platforms such as PatientsLikeMe (PLM) offer a venue for individuals with various diagnoses to share experiences and build community, though they may not be representative of the larger patient population. This potentially limits generalizability and raises concerns about the spread of misinformation, emphasizing the need for informed use and health care provider engagement.

Health-focused conversational agents in person-centered care: a review of apps.

Health-focused apps with chatbots ("healthbots") have a critical role in addressing gaps in quality healthcare. There is limited evidence on how such healthbots are developed and applied in practice. Our review of healthbots aims to classify types of healthbots, contexts of use, and their natural language processing capabilities. Eligible apps were those that were health-related, had an embedded text-based conversational agent, available in English, and were available for free download through the Google Play or Apple iOS store. Apps were identified using 42Matters software, a mobile app search engine. Apps were assessed using an evaluation framework addressing chatbot characteristics and natural language processing features. The review suggests uptake across 33 low- and high-income countries. Most healthbots are patient-facing, available on a mobile interface and provide a range of functions including health education and counselling support, assessment of symptoms, and assistance with tasks such as scheduling. Most of the 78 apps reviewed focus on primary care and mental health, only 6 (7.59%) had a theoretical underpinning, and 10 (12.35%) complied with health information privacy regulations. Our assessment indicated that only a few apps use machine learning and natural language processing approaches, despite such marketing claims. Most apps allowed for a finite-state input, where the dialogue is led by the system and follows a predetermined algorithm. Healthbots are potentially transformative in centering care around the user; however, they are in a nascent state of development and require further research on development, automation and adoption for a population-level health impact.