Cyclic Glycine-Proline Improves Memory and Reduces Amyloid Plaque Load in APP/PS1 Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative condition that is pathologically characterized by the presence of amyloid plaques and neurofibrillary tangles. Animal models of AD have been useful in understanding the disease process and in investigating the effects of compounds on pathology and behavior. APP/PS1 mice develop amyloid plaques and show memory impairment. Cyclic glycine-proline (cGP) is a cyclic dipeptide that is likely produced from a tripeptide, glycine-proline-glutamate, which itself is generated after proteolytic cleavage of insulin-like growth factor-1. Here, we show that cGP improves spatial memory and reduces amyloid plaque burden in APP/PS1 mice. The results thus suggest that cGP could potentially provide beneficial effects in AD.

Differences in temporal processing speeds between the right and left auditory cortex reflect the strength of recurrent synaptic connectivity.

Brain asymmetry in the sensitivity to spectrotemporal modulation is an established functional feature that underlies the perception of speech and music. The left auditory cortex (ACx) is believed to specialize in processing fast temporal components of speech sounds, and the right ACx slower components. However, the circuit features and neural computations behind these lateralized spectrotemporal processes are poorly understood. To answer these mechanistic questions we use mice, an animal model that captures some relevant features of human communication systems. In this study, we screened for circuit features that could subserve temporal integration differences between the left and right ACx. We mapped excitatory input to principal neurons in all cortical layers and found significantly stronger recurrent connections in the superficial layers of the right ACx compared to the left. We hypothesized that the underlying recurrent neural dynamics would exhibit differential characteristic timescales corresponding to their hemispheric specialization. To investigate, we recorded spike trains from awake mice and estimated the network time constants using a statistical method to combine evidence from multiple weak signal-to-noise ratio neurons. We found longer temporal integration windows in the superficial layers of the right ACx compared to the left as predicted by stronger recurrent excitation. Our study shows substantial evidence linking stronger recurrent synaptic connections to longer network timescales. These findings support speech processing theories that purport asymmetry in temporal integration is a crucial feature of lateralization in auditory processing.

Effects of a Tripeptide on Mitogen-Activated Protein Kinase and Glycogen Synthase Kinase Activation in a Cell Line Derived from the Foetal Hippocampus of a Trisomy 16 Mouse: an Animal Model of Down Syndrome.

Down syndrome (DS) is a developmental disorder that results from the trisomy of chromosome 21. DS patients show several abnormalities including cognitive deficits. Here, we show enhanced activation of the extracellular signal-regulated kinase (ERK), a kinase that critically regulates synaptic plasticity and memory, in a hippocampal cell line derived from trisomy 16 mouse foetus. In addition, these cells show enhanced activation of p38 mitogen-activated protein kinase (p38 MAPK). The hyper-activation of ERK and p38 MAPK is significantly reduced by a small peptide, Gly-Pro-Glu (GPE), derived from insulin-like growth factor-1. In addition, the trisomic cells show reduced level of inhibitory phosphorylation of glycogen synthase kinase-3ß (GSK-3ß), which is enhanced by GPE. Furthermore, the trisomic cells do not show ERK activation in response to KCl depolarization or forskolin treatment. Importantly, ERK activation by these stimuli is observed after GPE treatment of the cells. These results suggest that GPE may help reduce aberrant signalling in the trisomic neurons by affecting MAPK and GSK-3ß activation.

Development of a Subhuman Primate Brain Finite Element Model to Investigate Brain Injury Thresholds Induced by Head Rotation.

An anatomically detailed rhesus monkey brain FE model was developed to simulate in vivo responses of the brain of sub-human primates subjected to rotational accelerations resulting in diffuse axonal injury (DAI). The material properties used in the monkey model are those in the GHBMC 50th percentile male head model (Global Human Body Model Consortium). The angular loading simulations consisted of coronal, oblique and sagittal plane rotations with the center of rotation in neck to duplicate experimental conditions. Maximum principal strain (MPS) and Cumulative strain damage measure (CSDM) were analyzed for various white matter structures such as the cerebrum subcortical white matter, corpus callosum and brainstem. The MPS in coronal rotation were 45% to 54% higher in the brainstem, 8% to 48% higher in the corpus callosum, 13% to 22% higher in the white matter when compared to those in oblique and sagittal rotations, suggesting that more severe DAI was expected from coronal and oblique rotations as compared to that from sagittal rotation. The level 1+ DAI was associated with 1.3 to 1.42 MPS and 50% CSDM (0.5) responses in the brainstem, corpus callosum and cerebral white matter. The mass scaling method, sometimes referred to as Holbourn's inverse 2/3 power law, used for development of human brain injury criterion was evaluated to understand the effect of geometrical and anatomical differences between human and animal head. Based on simulations conducted with the animal and human models in three different planes - sagittal, coronal and horizontal - the scaling from animal to human models are not supported due to lack of geometrical similitude between the animal and human brains. Thus, the scaling method used in the development of brain injury criterion for rotational acceleration/velocity is unreliable.

Incidence, short-term outcome, and spatial distribution of stroke patients in Ludhiana, India.

OBJECTIVE: To estimate the incidence, short-term outcome, and spatial distribution of stroke patients and to evaluate the completeness of case ascertainment in Ludhiana. METHODS: This population-based prospective cohort study was conducted in Ludhiana, Punjab, Northwest India. All first-ever stroke patients (≥18 years) were included between March 2010 and March 2013 using WHO Stepwise Approach Surveillance methodology from the city. Stroke patient data were obtained from hospitals, scan centers, and general practitioners, and details of deaths from the Municipal Corporation. RESULTS: Out of 7,199 stroke patients recruited, 3,441 were included in final analysis. The mean age was 59 ± 15 years. The annual incidence rate was 140/100,000 (95% confidence interval [CI] 133-147) and age-adjusted incidence rate was 130/100,000 (95% CI 123-137). The annual incidence rate for stroke in the young (18-49 years) was 46/100,000 (95% CI 41-51). The case fatality at 28 days was 22%. Patients above 60 years of age (p = 0.03) and patients who were managed in public hospitals had poor survival (p = 0.01). Hot spots for cumulative incidence were seen in central and southern parts of the city, and hot spots for poor outcome were seen in the outskirts of the city. CONCLUSIONS: The incidence rates are similar to other studies from India. Stroke patient survival is poor in public hospitals. The finding of spatial analysis is of public health significance for stroke prevention and strengthening of stroke services.

Oxcarbazepine and fluoxetine protect against mouse models of obsessive compulsive disorder through modulation of cortical serotonin and CREB pathway.

The serotonergic system is suggested to be dysregulated in obsessive compulsive disorder (OCD) as selective serotonin reuptake inhibitors have emerged as the mainstay in the treatment of this disorder. Oxcarbazepine (OXC), a second generation antiepileptic drug, enhances hippocampal serotonin (5-HT) levels. The aim of the present study was to screen the anti-OCD effects of OXC on marble burying behaviour (MBB) and 8-OHDPAT-induced disruption of alternation, two most studied paradigms of OCD, in rodents. Here we show that 8-OHDPAT (2.8 mg/kg) significantly increases spontaneous alternation behaviour (SAB) score in a T-maze. Fluoxetine (FLX), an SSRI on chronic administration (10mg/kg, 21 days) restored the increase in SAB induced by 8-OHDPAT in mice which is in line with the findings earlier reported for rats. Hence, we present the first mouse model of OCD induced by 2.8 mg/kg of 8-OHDPAT. Chronic administration (21 days) of OXC (20 and 40 mg/kg) also restored the SAB disrupted by 8-OHDPAT which was comparable to FLX. Likewise in MBB test, FLX and OXC significantly reduced the number of marbles buried. 8-OHDPAT induced OCD was associated with a concomitant decrease in basal 5-HT levels (88%) and depletion of basal CREB (32%) in the frontal cortex. Chronic treatment with FLX and OXC effectively mitigated the lowering effects of 8-OHDPAT on cortical 5-HT, and enabled an efficient recovery in basal CREB levels. Our results on FLX and OXC provide the indication that their anti-OCD effects in part, might be elicited through modulation of 5HT levels and CREB pathway.