Behavioral and Metabolic Effects of ABCG4 KO in the APPswe,Ind (J9) Mouse Model of Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD) is complex and involves an imbalance between production and clearance of amyloid-ß peptides (Aß), resulting in accumulation of Aß in senile plaques. Hypercholesterolemia is a major risk factor for developing AD, with cholesterol shown to accumulate in senile plaques and increase production of Aß. ABCG4 is a member of the ATP-binding cassette transporters predominantly expressed in the CNS and has been suggested to play a role in cholesterol and Aß efflux from the brain. In this study, we bred Abcg4 knockout (KO) with the APPSwe,Ind (J9) mouse model of AD to test the hypothesis that loss of Abcg4 would exacerbate the AD phenotype. Unexpectedly, no differences were observed in novel object recognition (NOR) and novel object placement (NOP) behavioral tests, or on histologic examinations of brain tissues for senile plaque numbers. Furthermore, clearance of radiolabeled Aß from the brains did not differ between Abcg4 KO and control mice. Metabolic testing by indirect calorimetry, glucose tolerance test (GTT), and insulin tolerance test (ITT) were also mostly similar between groups with only a few mild metabolic differences noted. Overall, these data suggest that the loss of ABCG4 did not exacerbate the AD phenotype.

Strain in the Midbrain: Impact of Traumatic Brain Injury on the Central Serotonin System.

Traumatic brain injury (TBI) is a pervasive public health crisis that severely impacts the quality of life of affected individuals. Like peripheral forms of trauma, TBI results from extraordinarily heterogeneous environmental forces being imparted on the cranial space, resulting in heterogeneous disease pathologies. This has made therapies for TBI notoriously difficult to develop, and currently, there are no FDA-approved pharmacotherapies specifically for the acute or chronic treatment of TBI. TBI is associated with changes in cognition and can precipitate the onset of debilitating psychiatric disorders like major depressive disorder (MDD), generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD). Complicating these effects of TBI, FDA-approved pharmacotherapies utilized to treat these disorders often fail to reach the desired level of efficacy in the context of neurotrauma. Although a complicated association, decades of work have linked central serotonin (5-HT) neurotransmission as being involved in the etiology of a myriad of neuropsychiatric disorders, including MDD and GAD. 5-HT is a biogenic monoamine neurotransmitter that is highly conserved across scales of biology. Though the majority of 5-HT is isolated to peripheral sites such as the gastrointestinal (GI) tract, 5-HT neurotransmission within the CNS exerts exquisite control over diverse biological functions, including sleep, appetite and respiration, while simultaneously establishing normal mood, perception, and attention. Although several key studies have begun to elucidate how various forms of neurotrauma impact central 5-HT neurotransmission, a full determination of precisely how TBI disrupts the highly regulated dynamics of 5-HT neuron function and/or 5-HT neurotransmission has yet to be conceptually or experimentally resolved. The purpose of the current review is, therefore, to integrate the disparate bodies of 5-HT and TBI research and synthesize insight into how new combinatorial research regarding 5-HT neurotransmission and TBI may offer an informed perspective into the nature of TBI-induced neuropsychiatric complications.

Behavioral and metabolic and effects of ABCG4 KO in the APPswe,Ind (J9) mouse model of Alzheimer's disease.

The pathogenesis of Alzheimer's disease (AD) is complex and involves an imbalance between production and clearance of amyloid-ß peptides (Aß), resulting in accumulation of Aß in senile plaques. Hypercholesterolemia is a major risk factor for developing AD, with cholesterol shown to accumulate in senile plaques and increase production of Aß. ABCG4 is a member of the ATP-binding cassette transporters predominantly expressed in the CNS, and has been suggested to play a role in cholesterol and Aß efflux from the brain. In this study, we bred Abcg4 knockout (KO) with the APPSwe,Ind (J9) mouse model of AD to test the hypothesis that loss of Abcg4 would exacerbate the AD phenotype. Unexpectedly, no differences were observed in Novel object recognition (NOR) and Novel object placement (NOP) behavioral tests, or on histologic examinations of brain tissues for senile plaque numbers. Furthermore, clearance of radiolabeled Aß from the brains did not differ between Abcg4 KO and control mice. Metabolic testing by indirect calorimetry, glucose tolerance test (GTT) and insulin tolerance test (ITT), were also mostly similar between groups with only a few mild metabolic differences noted. Overall these data suggest that the loss of ABCG4 did not exacerbate the AD phenotype.

Increased Carbon Dioxide Respiration Prevents the Effects of Acceleration/Deceleration Elicited Mild Traumatic Brain Injury.

Acceleration/deceleration forces are a common component of various causes of mild traumatic brain injury (mTBI) and result in strain and shear forces on brain tissue. A small quantifiable volume dubbed the compensatory reserve volume (CRV) permits energy transmission to brain tissue during acceleration/deceleration events. The CRV is principally regulated by cerebral blood flow (CBF) and CBF is primarily determined by the concentration of inspired carbon dioxide (CO2). We hypothesized that experimental hypercapnia (i.e. increased inspired concentration of CO2) may act to prevent and mitigate the actions of acceleration/deceleration-induced TBI. To determine these effects C57Bl/6 mice underwent experimental hypercapnia whereby they were exposed to medical-grade atmospheric air or 5% CO2 immediately prior to an acceleration/deceleration-induced mTBI paradigm. mTBI results in significant increases in righting reflex time (RRT), reductions in core body temperature, and reductions in general locomotor activity-three hours post injury (hpi). Experimental hypercapnia immediately preceding mTBI was found to prevent mTBI-induced increases in RRT and reductions in core body temperature and general locomotor activity. Ribonucleic acid (RNA) sequencing conducted four hpi revealed that CO2 exposure prevented mTBI-induced transcriptional alterations of several targets related to oxidative stress, immune, and inflammatory signaling. Quantitative real-time PCR analysis confirmed the prevention of mTBI-induced increases in mitogen-activated protein kinase kinase kinase 6 and metallothionein-2. These initial proof of concept studies reveal that increases in inspired CO2 mitigate the detrimental contributions of acceleration/deceleration events in mTBI and may feasibly be translated in the future to humans using a medical device seeking to prevent mTBI among high-risk groups.

Effect of driver gas composition on production of scaled Friedlander waveforms in an open-ended shock tube model.

With the evolution of modern warfare and the increased use of improvised explosive devices (IEDs), there has been an increase in blast-induced traumatic brain injuries (bTBI) among military personnel and civilians. The increased prevalence of bTBI necessitates bTBI models that result in a properly scaled injury for the model organism being used. The primary laboratory model for bTBI is the shock tube, wherein a compressed gas ruptures a thin membrane, generating a shockwave. To generate a shock wave that is properly scaled from human to rodent subjects many pre-clinical models strive for a short duration and high peak overpressure while fitting a Friedlander waveform, the ideal representation of a blast wave. A large variety of factors have been experimentally characterized in attempts to create an ideal waveform, however we found current research on the gas composition being used to drive shock wave formation to be lacking. To better understand the effect the driver gas has on the waveform being produced, we utilized a previously established murine shock tube bTBI model in conjunction with several distinct driver gasses. In agreement with previous findings, helium produced a shock wave most closely fitting the Friedlander waveform in contrast to the plateau-like waveforms produced by some other gases. The peak static pressure at the exit of the shock tube and total pressure 5 cm from the exit have a strong negative correlation with the density of the gas being used: helium the least dense gas used produces the highest peak overpressure. Density of the driver gas also exerts a strong positive effect on the duration of the shock wave, with helium producing the shortest duration wave. Due to its ability to produce a Friedlander waveform and produce a waveform following proper injury scaling guidelines, helium is an ideal gas for use in shock tube models for bTBI.