Assessment of Nutritional Status of Under-Five Children in an Urban Area of South Delhi, India.

Introduction Malnutrition among children continues to be a severe public health problem worldwide, whether in a developing country like India or a developed nation. Correct estimation of the problem is a prerequisite to planning the measures to control it. Objective To estimate the prevalence of undernutrition among children under five years of age by utilizing the Composite Index of Anthropometric Failure and the WHO growth charts. Methods From January to March 2020, 1332 children under the age of five years participated in a facility-based, descriptive, cross-sectional study at Fatehpur Beri, Urban Primary Health Center. An anthropometric assessment for each participant was done as per the WHO criteria. The data were entered into a Microsoft Office Excel spreadsheet (Microsoft Corporation, Redmond, WA) and analyzed with WHO Anthro software (WHO, Geneva, Switzerland) and a licensed version of SPSS 21 (IBM Corp., Armonk, NY). Continuous data were expressed using appropriate measures of central tendency, while categorical data were expressed in either frequency or proportions. Results The mean age of the study participants was 23.04 ± 18.24 months, and males (53.3%) were more than (46.7%) females. The prevalence of being underweight was 24.5% (327/1332), of which 24.1% (79/327) of children were severely underweight. Of the total study participants, 27.3% (362/1332) were stunted, and 17.8% (237/1332) were wasted, of which 29.1% (69/237) were severely wasted. The prevalence of anthropometric failure was 45%. Conclusions According to the findings of this study, the prevalence of undernutrition among the study participants was substantial. Furthermore, considering weight for age as the sole criterion may underestimate the true prevalence of malnutrition. The findings have critical implications for future interventions and initiatives among children in India.

Clinico-epidemiological profile of women with high-risk pregnancy utilizing antenatal services in a rural primary health center in India.

Objective: Early detection and effective management of high-risk pregnancies can substantially contribute to the reduction of adverse maternal and fetal outcomes. This study aimed to determine the prevalence and clinical profile of women with high-risk pregnancies in rural areas who utilize antenatal services in a primary health center (PHC). Materials and Methods: A retrospective analysis was carried out over a six-month period by reviewing the mother and child protection cards maintained at the PHC's Maternal and Child Health Center. During the study period, 950 pregnant women were registered, of whom 793 were included in the study based on the completeness of the records. Data analysis was performed using the licensed Statistical Package for the Social Sciences (SPSS) software version 21.0. Results: The prevalence of high-risk pregnancy among the antenatal women was 272 (34.3%) with 95% CI [31.1-37.7]. Of the 272 women, 240 (88.2%) had a single high-risk factor, while 32 (11.8%) had more than one high-risk factor. The major factor contributing to high-risk pregnancy was hypothyroidism (43.7% with 95% CI [37.9-49.6]), followed by a previous lower segment Caesarean section (LSCS) (19.1%). Conclusion: The study found that the prevalence of high-risk pregnancies was 34.3% in this rural setting. The majority of high-risk pregnancies were due to hypothyroidism, followed by more than one previous LSCS or abortion. Further research is required to track high-risk pregnancy outcomes and investigate the newborn thyroid profile of women with hypothyroidism.

Study of aggression and its factors among school going adolescents of Delhi, India.

Background: Adolescence is an important developmental phase of life associated with various ideas and emotions filled with energy, many times spent in the form of aggressive behavior. Mental Health, as an important part of healthy well-being, cannot be ignored, and hence it becomes imperative to study aggression and associated factors among adolescents. Objective: To determine the prevalence of aggression among school-going adolescents and to study factors associated with aggression amongst study participants. Materials and Methods: A cross-sectional study was conducted using a self-administered semi-structured questionnaire having questions regarding socio-demographic data, details of friends, history of substance use etc. and the Buss and Perry Aggression Questionnaire (BPAQ). Data were analyzed using appropriate statistical tests. Ethical clearance was obtained from the Institutional Ethics Committee of Safdarjung Hospital, and informed written consent was taken from participants. Results: The study involved a total of 463 school-going adolescents with a mean age of 13.78 ± 2.06 years. More than half (50.5%) of the participants were found to be aggressive. Male gender, history of family member ever jailed, parent's argument in front of them, ever tried cigarette/smoking, being involved in some fight and provocation by friends for aggression were the factors found to be significantly associated with aggression. Conclusion: The prevalence of aggression among school-going adolescents of Delhi was quite high. There is a need to make the students aware about aggression and how to deal with it. A holistic approach may be adopted in which all authorities and stakeholders must work together to provide safer and nurturing environment to all students.

Role of handgrip strength testing in pre-anaesthetic check-up: A prospective cross-sectional study.

Background and Aims: Frailty has been known to be associated with postoperative adverse events and longer hospital length of stay (LOS). Hand grip strength (HGS) is one of the parameters of measuring frailty. The aim of the study was to correlate preoperative handgrip strength and 30-day outcome of patients undergoing major abdominal surgery. It also aimed to evaluate the role of the standard preoperative variables like metabolic equivalents, revised cardiac risk index (RCRI), serum albumin, and serum creatinine along with their association with HGS testing in determining the postoperative outcome in surgical patients. Material and Methods: This prospective observational study included 149 American Society of Anesthesiologists class III/IV patients presenting for major abdominal surgery. A mean of three measurements of dominant HGS using Camry hand dynamometer was measured. The patients were divided into groups: weak, normal, and strong depending on grip strength. Patients were followed for 30 days and postoperative outcome in terms of ventilatory support, admission to intensive care unit, cardiac complications, in-hospital mortality, and LOS were recorded. Observational data obtained were reported as mean value and analyzed using Student's t-test or Wilcoxon/Mann-Whitney Rank test. Associations between RCRI, serum albumin, and LOS with HGS were evaluated using logistic regression. Results: The hospital LOS was significantly longer in patients with weak HGS (15.11 ± 11.03 days versus 10 ± 5.71 days, P = 0.001). Patients with weak HGS had significantly lower mean serum albumin levels compared to normal HGS (P = 0.0001) and a statistically significant RCRI score (P = 0.013). Conclusion: HGS can be used as a preoperative test in predicting hospital LOS after major surgery.

An epidemiological study of domiciliary practices and health seeking behaviour among animal bite patients attending a hospital in Delhi.

Background and Objectives: Rabies, although a 100% fatal disease, is preventable with appropriate post-exposure prophylaxis. A hospital-based cross-sectional study was conducted among 360 animal bite patients in the anti-rabies clinic (ARC) of Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi (VMMC & SJH). Methods: A predesigned, pretested, structured questionnaire was administered by interview technique to assess the sociodemographic profile, health-seeking behavior, and the various domiciliary practices adopted by the animal bite patients. Results: Out of 360 study participants (348; 96.7%) visited a health facility (government/private) after an animal-bite incident. Of the 241 study participants who washed their wounds, 131 (54.4%) had washed the wound using soap and water and 216 (89.6%) had washed the wound for less than 5 min. Chili paste (128; 35.6%) was the most commonly used household remedy. Interpretation and Conclusions: It was observed that a considerable segment of the study population approached health care facilities for vaccination following animal bite but did not practice the correct wound-washing practices immediately after the incident, and a sizeable proportion of the study participants resorted to non-allopathic practices (e.g., chili paste) as a measure of first aid to manage animal bite wounds. No association was found between the sociodemographic determinants and domiciliary practices and health-seeking behavior (P > 0.05). As rabies is a preventable disease, increasing awareness pertaining to its prevention may prove to be beneficial in reducing the morbidity and mortality.

Compliance to post-exposure prophylaxis among animal bite patients - A hospital-based epidemiological study.

Background and Objectives: Although rabies is a 100% fatal disease, it is preventable with appropriate and timely post-exposure prophylaxis (PEP). A hospital-based study was conducted among 360 animal bite patients in the Anti-Rabies Clinic (ARC) of Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi (VMMC and SJH). Materials and Methods: A predesigned, pretested, structured questionnaire was administered by the interview technique to assess the compliance to PEP among the animal bite patients attending the ARC, which comprised assessment of wound washing practices adopted by the animal bite patients, administration of rabies immunoglobulin (RIG), and compliance to full course of anti-rabies vaccination (ARV). Results: Out of 360 study participants, 131 (54.4%) had washed the wound using soap and water and 216 (89.6%) had washed the wound for less than 5 min. The compliance to the full course of ARV was seen among 172 (47.8%) study participants, whereas 164 (45.5%) were found to be non-compliant and 24 (6.7%) were found to be delayed compliant. Conclusions: It was observed that a considerable segment of the study population did not practice the correct wound washing practices, and only about half of the total study participants (172; 47.8%) were found to be compliant to the full course of ARV. As rabies is a 100% preventable disease, increasing awareness pertaining to appropriate PEP may prove to be beneficial in improving the compliance to PEP and reducing the burden of mortality.

Comparative evaluation of oral tramadol and gabapentin for prophylaxis of post-spinal shivering.

BACKGROUND AND AIMS: Shivering in the peri-operative period is a common problem which is associated with various complications. Prophylaxis of shivering can thus help in reducing the cost and risk of complications. The present study was designed to compare prophylactic oral gabapentin, tramadol and placebo for prevention of post-spinal shivering. METHODS: A total of 150 adult patients of either sex belonging to American Society of Anesthesiologists physical status I-III scheduled for elective orthopaedic surgeries were randomised to receive tramadol 100 mg (group A), gabapentin 600 mg (group B) or placebo (group C) orally 30 min before administration of spinal anaesthesia. The primary outcome was to study the incidence and severity of shivering,whereas the secondary outcome was to evaluate the incidence of adverse effects. Data were analysed by analysis of variance test, Student t-test, Mann-Whitney U test and Chi-square tests. RESULTS: Incidence of shivering was comparable among groups A and B (P = 0.8) whereas it was significantly less than in group C (P = 0.00). Severity of shivering (grade 1 and 2) was comparable in all the groups (P = 0.6 and 0.36), whereas shivering grade 3 and grade 4 was significantly lesser in groups A and B as compared to group C (P = 0.01 and 0.01). The incidence of nausea and vomiting was more in group A (26%) as compared to group B (20%) (P = 0.48) but was significantly lesser than group C (48%) (P = 0.01). Incidence of sedation (sedation score ≥2) was significantly more in group B (22%) as compared to group A (4%) and group C (0%). CONCLUSION: Prophylactic oral gabapentin 600 mg and tramadol 100 mg are equally effective for prevention of post-spinal shivering.

Disruption of the blood-brain barrier in 22q11.2 deletion syndrome.

Neuroimmune dysregulation is implicated in neuropsychiatric disorders including schizophrenia. As the blood-brain barrier is the immunological interface between the brain and the periphery, we investigated whether this vascular phenotype is intrinsically compromised in the most common genetic risk factor for schizophrenia, the 22q11.2 deletion syndrome (22qDS). Blood-brain barrier like endothelium differentiated from human 22qDS+schizophrenia-induced pluripotent stem cells exhibited impaired barrier integrity, a phenotype substantiated in a mouse model of 22qDS. The proinflammatory intercellular adhesion molecule-1 was upregulated in 22qDS+schizophrenia-induced blood-brain barrier and in 22qDS mice, indicating compromise of the blood-brain barrier immune privilege. This immune imbalance resulted in increased migration/activation of leucocytes crossing the 22qDS+schizophrenia blood-brain barrier. We also found heightened astrocyte activation in murine 22qDS, suggesting that the blood-brain barrier promotes astrocyte-mediated neuroinflammation. Finally, we substantiated these findings in post-mortem 22qDS brain tissue. Overall, the barrier-promoting and immune privilege properties of the 22qDS blood-brain barrier are compromised, and this might increase the risk for neuropsychiatric disease.

The hedgehog pathway suppresses neuropathogenesis in CD4 T cell-driven inflammation.

The concerted actions of the CNS and the immune system are essential to coordinating the outcome of neuroinflammatory responses. Yet, the precise mechanisms involved in this crosstalk and their contribution to the pathophysiology of neuroinflammatory diseases largely elude us. Here, we show that the CNS-endogenous hedgehog pathway, a signal triggered as part of the host response during the inflammatory phase of multiple sclerosis and experimental autoimmune encephalomyelitis, attenuates the pathogenicity of human and mouse effector CD4 T cells by regulating their production of inflammatory cytokines. Using a murine genetic model, in which the hedgehog signalling is compromised in CD4 T cells, we show that the hedgehog pathway acts on CD4 T cells to suppress the pathogenic hallmarks of autoimmune neuroinflammation, including demyelination and axonal damage, and thus mitigates the development of experimental autoimmune encephalomyelitis. Impairment of hedgehog signalling in CD4 T cells exacerbates brain-brainstem-cerebellum inflammation and leads to the development of atypical disease. Moreover, we present evidence that hedgehog signalling regulates the pathogenic profile of CD4 T cells by limiting their production of the inflammatory cytokines granulocyte-macrophage colony-stimulating factor and interferon-γ and by antagonizing their inflammatory program at the transcriptome level. Likewise, hedgehog signalling attenuates the inflammatory phenotype of human CD4 memory T cells. From a therapeutic point of view, our study underlines the potential of harnessing the hedgehog pathway to counteract ongoing excessive CNS inflammation, as systemic administration of a hedgehog agonist after disease onset effectively halts disease progression and significantly reduces neuroinflammation and the underlying neuropathology. We thus unveil a previously unrecognized role for the hedgehog pathway in regulating pathogenic inflammation within the CNS and propose to exploit its ability to modulate this neuroimmune network as a strategy to limit the progression of ongoing neuroinflammation.

Determinants of substance use among young people attending an urban primary health center in Delhi.

INTRODUCTION: Substance abuse remains one of the major challenges in young people, as it is one of the top five causes of disability-adjusted life years (DALY). The present study aims to find the prevalence and determinants of substance use among young people attending an urban primary health center in Delhi. METHODOLOGY: Systematic random sampling was used to enroll the calculated sample size of 190. Substance use was assessed using ASSIST (an Alcohol Smoking Substance Involvement Screening Tool) and brief intervention was given based on the standard guidelines of ASSIST. The total score among the substance users is calculated and divided into Grades 1, 2 or 3. Log binomial regression was performed to quantify the association between substance use and covariates such as age, sex, education, occupation, family history of substance use, socio-economic status and family type. The association was expressed in odds ratio (OR) with 95 percent confidence interval (CI). RESULT: The mean age of study participants was 18.6 ± 4.1, ranges from 10 to 24 years. Out of 48 substance users, 43.7% were consuming only tobacco, 22.9% were consuming only alcohol and 33.3% were polysubstance users. The history of substance use among family members of participants was found to be 46.3%. Median substance involvement score of tobacco, alcohol and cannabis users was 19 (IQR: 14.5-22), 19 (IQR: 13.5-25) and 22.5 (IQR: 22-23), respectively. Among tobacco users, 2.7% were Grade 1 and 7.2% were Grade 2. Four (16%), 20 (80%) and one (4%) of alcohol users were Grades 1, 2 and 3, respectively. Among the cannabis users, four (100%) were in the Grade 2 category. The median age of initiation of substance use among users was 16 (range 13-21) years. The analysis shows substance use was almost 25 times (adjusted OR = 25.84, 95% CI 5.65-118.09) more common among males and it increase by 2.5 times with a decrease in socio-economic status (adjusted OR = 2.52, 95% CI 1.27-5.02) and the result is significant. The substance use was almost 7 times higher when there is a family history of substance usage (adjusted OR = 7.40, 95% CI 2.15-25.4). Residential and marital status were not significantly associated with substance use. CONCLUSION: Male sex, lower socio-economic status, participants currently not going to school/college, family history of substance use were found to be significant predictors of substance use among the study participants.

Thyroid Hormone Regulation of Adult Neurogenesis.

Thyroid hormone is classically known to play a crucial role in neurodevelopment. The potent effects that thyroid hormone exerts on the adult mammalian brain have been uncovered relatively recently, including an important role in the modulation of progenitor development in adult neurogenic niches. This chapter extensively reviews the current understanding of the influence of thyroid hormone on distinct stages of adult progenitor development in the subgranular zone (SGZ) of the hippocampus and subventricular zone (SVZ) that lines the lateral ventricles. We discuss the role of specific thyroid hormone receptor isoforms, in particular TRα1, which modulates cell cycle exit in neural stem cells, progenitor survival, and cell fate choice, with both a discrete and overlapping nature of regulation noted in SGZ and SVZ progenitors. The balance between liganded and unliganded TRα1 can evoke differing consequences for adult progenitor development, and the relevance of this to conditions such as adult-onset hypothyroidism, wherein unliganded thyroid hormone receptors (TRs) dominate, is also a focus of discussion. Although a detailed molecular understanding of the specific thyroid hormone target genes that contribute to the neurogenic actions of thyroid hormone is currently lacking, we highlight the current state of knowledge and discuss avenues for future investigation. The goal of this chapter is to provide a comprehensive and detailed analysis of the effects of thyroid hormone on adult neurogenesis, to discuss putative molecular mechanisms that mediate these effects, and the behavioral, functional, and clinical implications of the neurogenic actions of thyroid hormone.

The miRNA miR-34a enhances HIV-1 replication by targeting PNUTS/PPP1R10, which negatively regulates HIV-1 transcriptional complex formation.

HIV-1 relies heavily on the host cellular machinery for its replication. During infection, HIV-1 is known to modulate the host-cell miRNA profile. One of the miRNAs, miR-34a, is up-regulated by HIV-1 in T-cells as suggested by miRNA microarray studies. However, the functional consequences and the mechanism behind this phenomenon were not explored. The present study shows that HIV-1 enhances miR-34a in a time-dependent manner in T-cells. Our overexpression and knockdown-based experimental results suggest that miR-34a promotes HIV-1 replication in T-cells. Hence, there is a positive feedback loop between miR-34a and HIV-1 replication. We show that the mechanism of action of miR-34a in HIV-1 replication involves a cellular protein, the phosphatase 1 nuclear-targeting subunit (PNUTS). PNUTS expression levels decrease with the progression of HIV-1 infection in T-cells. Also, the overexpression of PNUTS potently inhibits HIV-1 replication in a dose-dependent manner. We report for the first time that PNUTS negatively regulates HIV-1 transcription by inhibiting the assembly of core components of the transcription elongation factor P-TEFb, i.e. cyclin T1 and CDK9. Thus, HIV-1 increases miR-34a expression in cells to overcome the inhibitory effect of PNUTS on HIV-1 transcription. So, the present study provides new mechanistic details with regard to our understanding of a complex interplay between miR-34a and the HIV-1 transcription machinery involving PNUTS.

Perspectives on thyroid hormone action in adult neurogenesis.

Thyroid hormone exhibits profound effects on neural progenitor turnover, survival, maturation, and differentiation during perinatal development. Studies over the past decade have revealed that thyroid hormone continues to retain an important influence on progenitors within the neurogenic niches of the adult mammalian brain. The focus of the current review is to critically examine and summarize the current state of understanding of the role of thyroid hormone in regulating adult neurogenesis within the major neurogenic niches of the subgranular zone in the hippocampus and the subventricular zone lining the lateral ventricles. We review in depth the studies that highlight a role for thyroid hormone, in particular the TRα1 receptor isoform, in regulating progenitor survival and commitment to a neuronal fate. We also discuss putative models for the mechanism of action of thyroid hormone/TRα1 on specific stages of subgranular zone and subventricular zone progenitor development, and highlight potential thyroid hormone responsive target genes that may contribute to the neurogenic effects of thyroid hormone. The effects of thyroid hormone on adult neurogenesis are discussed in the context of a potential role of these effects in the cognitive- and mood-related consequences of thyroid hormone dysfunction. Finally, we detail hitherto unexplored aspects of the effects of thyroid hormone on adult neurogenesis that provide impetus for future studies to gain a deeper mechanistic insight into the neurogenic effects of thyroid hormone. Thyroid hormone regulation of adult neurogenesis in the mammalian brain exhibits both unique and overlapping effects within distinct neurogenic niches. Thyroid hormone regulates hippocampal subgranular zone (SGZ) progenitor survival and neuronal cell fate acquisition and influences subventricular zone (SVZ) progenitor cell turnover, cell cycle exit, and neuronal cell fate acquisition. In this review, we summarize, critically discuss and highlight open questions in regard to thyroid hormone regulation of adult neurogenesis.

Genetic characterization of natural variants of Vpu from HIV-1 infected individuals from Northern India and their impact on virus release and cell death.

BACKGROUND: Genetic studies reveal that vpu is one of the most variable regions in HIV-1 genome. Functional studies have been carried out mostly with Vpu derived from laboratory adapted subtype B pNL 4-3 virus. The rationale of this study was to characterize genetic variations that are present in the vpu gene from HIV-1 infected individuals from North-India (Punjab/Haryana) and determine their functional relevance. METHODS: Functionally intact vpu gene variants were PCR amplified from genomic DNA of HIV-1 infected individuals. These variants were then subjected to genetic analysis and unique representative variants were cloned under CMV promoter containing expression vector as well as into pNL 4-3 HIV-1 virus for intracellular expression studies. These variants were characterized with respect to their ability to promote virus release as well as cell death. RESULTS: Based on phylogenetic analysis and extensive polymorphisms with respect to consensus Vpu B and C, we were able to arbitrarily assign variants into two major groups (B and C). The group B variants always showed significantly higher virus release activity and exhibited moderate levels of cell death. On the other hand, group C variants displayed lower virus release activity but greater cell death potential. Interestingly, Vpu variants with a natural S61A mutation showed greater intracellular stability. These variants also exhibited significant reduction in their intracellular ubiquitination and caused greater virus release. Another group C variant that possessed a non-functional ß-TrcP binding motif due to two critical serine residues (S52 and S56) being substituted with isoleucine residues, showed reduced virus release activity but modest cytotoxic activity. CONCLUSIONS: The natural variations exhibited by our Vpu variants involve extensive polymorphism characterized by substitution and deletions that contribute toward positive selection. We identified two major groups and an extremely rare ß-TrcP binding motif mutant that show widely varying biological activities with potential implications for conferring subtype-specific pathogenesis.

Thyroid hormone regulates the expression of the sonic hedgehog signaling pathway in the embryonic and adult Mammalian brain.

Thyroid hormone is important for development and plasticity in the immature and adult mammalian brain. Several thyroid hormone-responsive genes are regulated during specific developmental time windows, with relatively few influenced across the lifespan. We provide novel evidence that thyroid hormone regulates expression of the key developmental morphogen sonic hedgehog (Shh), and its coreceptors patched (Ptc) and smoothened (Smo), in the early embryonic and adult forebrain. Maternal hypo- and hyperthyroidism bidirectionally influenced Shh mRNA in embryonic forebrain signaling centers at stages before fetal thyroid hormone synthesis. Further, Smo and Ptc expression were significantly decreased in the forebrain of embryos derived from hypothyroid dams. Adult-onset thyroid hormone perturbations also regulated expression of the Shh pathway bidirectionally, with a significant induction of Shh, Ptc, and Smo after hyperthyroidism and a decline in Smo expression in the hypothyroid brain. Short-term T3 administration resulted in a significant induction of cortical Shh mRNA expression and also enhanced reporter gene expression in Shh(+/LacZ) mice. Further, acute T3 treatment of cortical neuronal cultures resulted in a rapid and significant increase in Shh mRNA, suggesting direct effects. Chromatin immunoprecipitation assays performed on adult neocortex indicated enhanced histone acetylation at the Shh promoter after acute T3 administration, providing further support that Shh is a thyroid hormone-responsive gene. Our results indicate that maternal and adult-onset perturbations of euthyroid status cause robust and region-specific changes in the Shh pathway in the embryonic and adult forebrain, implicating Shh as a possible mechanistic link for specific neurodevelopmental effects of thyroid hormone.

Loss of thyroid hormone receptor ß is associated with increased progenitor proliferation and NeuroD positive cell number in the adult hippocampus.

Adult hippocampal neurogenesis is modulated by perturbations in thyroid hormone status; however the role of specific thyroid hormone receptors (TRs) in this process is not completely understood. We show here that loss of the TRß gene results in a significant increase in the proliferation of adult hippocampal progenitors, without any change in immature neuron number or in the neuronal and glial differentiation of progenitors. Using the mitotic marker 5'-bromo-2-deoxyuridine (BrdU) or the endogenous cell cycle marker, proliferating cell nuclear antigen (PCNA), we find a significant increase in the number of BrdU- and PCNA-immunopositive cells within the subgranular zone (SGZ) of the dentate gyrus subfield in TRß-/- mice. Further, we find that TRß-/- mice exhibit a significant increase in the numbers of NeuroD-positive cells within the SGZ, suggesting that the increased numbers of proliferating progenitors translate into enhanced numbers of neuroblasts. Interestingly, the number of BrdU-positive cells that persist 4 weeks post-BrdU injection is unaltered in TRß-/- mice, indicating that the enhanced proliferation does not result in increased hippocampal neurogenesis. This is also supported by the evidence of no change in the numbers of cells expressing markers of immature neurons such as doublecortin or polysialylated neural cell adhesion molecule. Furthermore, no change is observed in the neuronal or glial differentiation of BrdU-positive cells in the TRß-/- mice. Taken together, our results provide novel evidence for a role of TRß in modulating hippocampal progenitor cell division, and implicate this receptor in the effects of thyroid hormone on adult hippocampal neurogenesis.

Unliganded thyroid hormone receptor alpha1 impairs adult hippocampal neurogenesis.

Thyroid hormone regulates adult hippocampal neurogenesis, a process involved in key functions, such as learning, memory, and mood regulation. We addressed the role of thyroid hormone receptor TRα1 in adult hippocampal neurogenesis, using mice harboring a TRα1 null allele (TRα1(-/-)), overexpressing TRα1 6-fold (TRα2(-/-)), and a mutant TRα1 (TRα1(+/m)) with a 10-fold lower affinity to the ligand. While hippocampal progenitor proliferation was unaltered, TRα1(-/-) mice exhibited a significant increase in doublecortin-positive immature neurons and increased survival of bromodeoxyuridine-positive (BrdU(+)) progenitors as compared to wild-type controls. In contrast, the TRα1(+/m) and the TRα2(-/-) mice, where the overexpressed TRα1 acts as an aporeceptor, showed a significant decline in surviving BrdU(+) progenitors. TRα1(-/-) and TRα2(-/-) mice showed opposing effects on neurogenic markers like polysialylated neural cell adhesion molecule and stathmin. The decreased progenitor survival in the TRα2(-/-) and TRα1(+/m) mice could be rescued by thyroid hormone treatment, as was the decline in neuronal differentiation seen in the TRα1(+/m) mice. These mice also exhibited a decrease in NeuroD(+) cell numbers in the dentate gyrus, suggesting an effect on early postmitotic progenitors. Our results provide the first evidence of a role for unliganded TRα1 in modulating the deleterious effects of hypothyroidism on adult hippocampal neurogenesis.