Showing papers by "Jacob Raber published in 2018"

Dlx1/2 and Otp coordinate the production of hypothalamic GHRH- and AgRP-neurons.

Abstract: Despite critical roles of the hypothalamic arcuate neurons in controlling the growth and energy homeostasis, the gene regulatory network directing their development remains unclear. Here we report that the transcription factors Dlx1/2 and Otp coordinate the balanced generation of the two functionally related neurons in the hypothalamic arcuate nucleus, GHRH-neurons promoting the growth and AgRP-neurons controlling the feeding and energy expenditure. Dlx1/2-deficient mice show a loss-of-GHRH-neurons and an increase of AgRP-neurons, and consistently develop dwarfism and consume less energy. These results indicate that Dlx1/2 are crucial for specifying the GHRH-neuronal identity and, simultaneously, for suppressing AgRP-neuronal fate. We further show that Otp is required for the generation of AgRP-neurons and that Dlx1/2 repress the expression of Otp by directly binding the Otp gene. Together, our study demonstrates that the identity of GHRH- and AgRP-neurons is synchronously specified and segregated by the Dlx1/2-Otp gene regulatory axis.

Effects of sub-chronic MPTP exposure on behavioral and cognitive performance and the microbiome of wild-type and mGlu8 knockout female and male mice

Abstract: Motor dysfunction is a hallmark of Parkinson's disease (PD); however, non-motor symptoms such as gastrointestinal dysfunction often arise prior to motor symptoms. Alterations in the gut microbiome have been proposed as the earliest event in PD pathogenesis. PD symptoms often demonstrate sex differences. Glutamatergic neurotransmission has long been linked to PD pathology. Metabotropic glutamate receptors (mGlu), a family of G protein-coupled receptors, are divided into three groups, with group III mGlu receptors mainly localized presynaptically where they can inhibit glutamate release in the CNS as well as in the gut. Additionally, the gut microbiome can communicate with the CNS via the gut-brain axis. Here, we assessed whether deficiency of metabotropic glutamate receptor 8 (mGlu8), group III mGlu, modulates the effects of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on behavioral and cognitive performance in female and male mice. We studied whether these effects are associated with changes in striatal tyrosine hydroxylase (TH) levels and the gut microbiome. Two-week sub-chronic MPTP increased activity of female and male wild-type (WT) and mGlu8 knockout (KO) mice in the open field. MPTP also showed genotype- and sex-dependent effects. MPTP increased the time WT, but not KO, females and males spent exploring objects. In WT mice, MPTP improved sensorimotor function in males but impaired it in females. Further, MPTP impaired cued fear memory in WT, but not KO, male mice. MPTP reduced striatal TH levels in WT and KO mice but these effects were only pronounced in males. MPTP treatment and genotype affected the diversity of the gut microbiome. In addition, there were significant associations between microbiome α-diversity and sensorimotor performance, as well as microbiome composition and fear learning. These results indicate that specific taxa may directly affect motor and fear learning or that the same physiological effects that enhance both forms of learning also alter diversity of the gut microbiome. MPTP's effect on motor and cognitive performance may then be, at least in part, be mediated by the gut microbiome. These data also support mGlu8 as a novel therapeutic target for PD and highlight the importance of including both sexes in preclinical studies.

Detrimental Effects of Helium Ion Irradiation on Cognitive Performance and Cortical Levels of MAP-2 in B6D2F1 Mice.

Abstract: The space radiation environment includes helium (4He) ions that may impact brain function. As little is known about the effects of exposures to 4He ions on the brain, we assessed the behavioral and cognitive performance of C57BL/6J × DBA2/J F1 (B6D2F1) mice three months following irradiation with 4He ions (250 MeV/n; linear energy transfer (LET) = 1.6 keV/μm; 0, 21, 42 or 168 cGy). Sham-irradiated mice and mice irradiated with 21 or 168 cGy showed novel object recognition, but mice irradiated with 42 cGy did not. In the passive avoidance test, mice received a slight foot shock in a dark compartment, and latency to re-enter that compartment was assessed 24 h later. Sham-irradiated mice and mice irradiated with 21 or 42 cGy showed a higher latency on Day 2 than Day 1, but the latency to enter the dark compartment in mice irradiated with 168 cGy was comparable on both days. 4He ion irradiation, at 42 and 168 cGy, reduced the levels of the dendritic marker microtubule-associated protein-2 (MAP-2) in the cortex. There was an effect of radiation on apolipoprotein E (apoE) levels in the hippocampus and cortex, with higher apoE levels in mice irradiated at 42 cGy than 168 cGy and a trend towards higher apoE levels in mice irradiated at 21 than 168 cGy. In addition, in the hippocampus, there was a trend towards a negative correlation between MAP-2 and apoE levels. While reduced levels of MAP-2 in the cortex might have contributed to the altered performance in the passive avoidance test, it does not seem sufficient to do so. The higher hippocampal and cortical apoE levels in mice irradiated at 42 than 168 cGy might have served as a compensatory protective response preserving their passive avoidance memory. Thus, there were no alterations in behavioral performance in the open filed or depressive-like behavior in the forced swim test, while cognitive impairments were seen in the object recognition and passive avoidance tests, but not in the contextual or cued fear conditioning tests. Taken together, the results indicate that some aspects of cognitive performance are altered in male mice exposed to 4He ions, but that the response is task-dependent. Furthermore, the sensitive doses can vary within each task in a non-linear fashion. This highlights the importance of assessing the cognitive and behavioral effects of charged particle exposure with a variety of assays and at multiple doses, given the possibility that lower doses may be more damaging due to the absence of induced compensatory mechanisms at higher doses.

Space Radiation Alters Genotype-Phenotype Correlations in Fear Learning and Memory Tests.

Abstract: Behavioral and cognitive traits have a genetic component even though contributions from individual genes and genomic loci are in many cases modest. Changes in the environment can alter genotype-phenotype relationships. Space travel, which includes exposure to ionizing radiation, constitutes environmental challenges and is expected to induce not only dramatic behavioral and cognitive changes but also has the potential to induce physical DNA damage. In this study, we utilized a genetically heterogeneous mouse model, dense genotype data, and shifting environmental challenges, including ionizing radiation exposure, to explore and quantify the size and stability of the genetic component of fear learning and memory-related measures. Exposure to ionizing radiation and other external stressors altered the genotype-phenotype correlations, although different behavioral and cognitive measures were affected to different extents. Utilizing an integrative genomic approach, we identified pathways and functional ontology categories associated with these behavioral and cognitive measures.

Integration of Human Eye-Tracking Responses and Object Recognition Test Performance

Abstract: Object recognition tasks can be used as sensitive measures of rodent cognitive ability. We have developed a version of this task that can be used to study human cognitive ability, the Novel Image Novel Location [NINL] test. In the test, study participants are first shown a series of panels with photographs displayed in three of the four quadrants of each panel. Participants are subsequently shown a series of panels that include some that are identical to the panels in the first set (no change condition), some that contain an image in the panel shown before but placed in a novel location (novel location condition) and some containing a novel image (novel image condition). The study participants are asked whether they noticed a change and, if they did, the nature of the change that they noticed. As described in this chapter, we found that eye-tracking responses can correlate with successful and unsuccessful learning and memory performance on the NINL test. These finding hold promise for assessments of participants who lack sufficient language or motor skills, such as touching a computer or tablet screen, that might be affected by age, language or neurological condition.