Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition

GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2^−/−) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2^−/− mice show cortical PV⁺ interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2^−/− mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2^−/− caudoventral hippocampus reverses these psychosis-relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.Precursors of most γ-aminobutyric acid (GABA)-releasing interneurons of the cerebral cortex and the hippocampus originate in the embryonic medial ganglionic eminence (MGE) (1–3). A subpopulation of MGE-derived cells differentiates into fast-spiking, parvalbumin-expressing (PV⁺) interneurons that tightly regulate the activity and synchronization of cortical projection neurons (2, 4). Structural and functional deficits in PV⁺ interneurons are hypothesized as a pathophysiological mechanism in schizophrenia and psychotic disorders (4–6).Although psychotic disorders are clearly heterogeneous in etiology, disinhibition within temporolimbic cortical circuits is postulated as a core pathophysiology underlying positive symptoms (e.g., delusions and hallucinations) and a subset of cognitive disturbances that manifest with psychosis (4, 5, 7). Postmortem studies of brains from individuals with psychotic disorders show reduced molecular markers of the number and/or function of PV⁺ interneurons in the hippocampus (6, 8). Consistent with these observations, basal metabolic activity in the hippocampus, as measured with functional magnetic resonance imaging (fMRI), is increased in schizophrenia, a phenotype that predicts psychosis and positive symptom severity (5, 7). This abnormal resting activity is postulated to underlie abnormal recruitment of hippocampal circuits during cognitive performance (5, 9). Striatal dopamine (DA) release capacity is also increased and correlated with positive symptoms in schizophrenia and its risk states (10, 11). Importantly, hippocampal hyperactivity may contribute to DA dysregulation (12), because rodent studies show that caudoventral hippocampal (in the primate, anterior hippocampal) efferents regulate the activity of DA neurons and medial striatal DA release (13, 14).Thus, converging evidence implicates hippocampal disinhibition in the abnormal striatal DA transmission and cognitive impairment in schizophrenia. However, the role of hippocampal inhibitory interneurons in psychosis-relevant circuitry remains to be established. To this end, we used the cyclin D2 (Ccnd2) knockout mouse model (15), which displays a relatively selective deficit in cortical PV⁺ interneurons, and transplantation of interneuron precursors from the MGE to elucidate relationships between reduced hippocampal GABA interneuron function and multiple psychosis-relevant phenotypes, and to explore a novel treatment strategy for psychosis.     

Exploring the potential of a conditional cash transfer intervention to reduce HIV risk among young women in Iringa,Tanzania

Cash transfer programs seek to alter structural determinants of HIV risk such as poverty and gender inequality. We sought to explore the feasibility and potential effectiveness of a cash transfer intervention for young women as part of combination HIV prevention in Iringa, Tanzania. Qualitative, in-depth interviews were conducted with 116 stakeholders and residents from the region, including key informants, service delivery users, and members of key populations. Most respondents felt a cash transfer program would assist young women in Iringa to have more control over sexual decision-making and reduce poverty-driven transactional sex. Respondents were divided on who should receive funds: young women themselves, their parents/guardians, or community leaders. Cash amounts and suggested target groups varied, and several respondents suggested providing microcredit or small business capital instead of cash. Potential concerns included jealousy, dependency, and corruption. However, most respondents felt that some intervention was needed to address underlying poverty driving some sexual risk behavior. A cash transfer program could fill this role, ultimately reducing HIV, sexually transmitted infections, and unintended pregnancies. As increased attention is given to economic and structural interventions for HIV prevention, local input and knowledge should be considered in a program design.     

Combining physical performance and Functional Movement Screen testing to identify elite junior Australian Football athletes at risk of injury

The Functional Movement Screen (FMS) and physical performance testing are often suggested to be related to sports injury risk. This study explored if the combination of FMS and physical performance testing improved identification of non-contact injury risk over FMS testing alone in an elite junior Australian football cohort. Over a 3-year period, 573 players completed pre-season injury history questionnaires, FMS, physical performance testing (20-m sprint, vertical jump, planned agility testing, and shuttle run test), and subsequent in-season injury surveillance. Results: Neither previous injury or FMS score <14 were related to an increased risk of subsequent injury in isolation. The combination of FMS composite score ≤14 and previous injury moderately increased the risk of injury (Hazard ratio [HR] = 2.22 [1.09-4.54]). None of the physical performance measures improved the ability to predict injuries based on FMS composite score. FMS asymmetry was only associated with injury when combined with previous injury and vertical jump performance. Players with ≥1 FMS asymmetry and history of previous injury experienced a large increase in injury risk when vertical jump was poor (HR = 4.26 [1.35-13.42]) or good (HR = 3.17 [1.08-9.29]). Players with a combination of a good vertical jump, no previous injury, and no FMS asymmetries were also at moderately increased risk of injury (HR = 3.41 [1.11-10.42]). No physical performance tests improved the ability to identify non-contact injury risk using an FMS composite score threshold. However, a U-shaped relationship between vertical jump and injury risk was identified with both poor and good vertical jump height associated with a moderate-large increase in non-contact injury risk in the presence of ≥1 asymmetrical FMS sub-test.