Mutations in human ZIP14 have been linked to symptoms of the early onset of Parkinsonism and Dystonia. This phenotype is likely related to excess manganese accumulation in the CNS. The metal transporter ZIP14 (SLC39A14) is viewed primarily as a zinc transporter that is inducible via proinflammatory stimuli. In vitro evidence shows that ZIP14 can also transport manganese. To examine a role for ZIP14 in manganese homeostasis, we used Zip14 knock-out (KO) male and female mice to conduct comparative metabolic, imaging, and functional studies. Manganese accumulation was fourfold to fivefold higher in brains of Zip14 KO mice compared with young adult wild-type mice. There was less accumulation of subcutaneously administered 54 Mn in the liver, gallbladder, and gastrointestinal tract of the KO mice, suggesting that manganese elimination is impaired with Zip14 ablation. Impaired elimination creates the opportunity for atypical manganese accumulation in tissues, including the brain. The intensity of MR images from brains of the Zip14 KO mice is indicative of major manganese accumulation. In agreement with excessive manganese accumulation was the impaired motor function observed in the Zip14 KO mice. These results also demonstrate that ZIP14 is not essential for manganese uptake by the brain. Nevertheless, the upregulation of signatures of brain injury observed in the Zip14 KO mice demonstrates that normal ZIP14 function is an essential factor required to prevent manganese-linked neurodegeneration.

Purpose In diffusion-weighted MRI studies of neural tissue, the classical model assumes the statistical mechanics of Brownian motion and predicts a monoexponential signal decay. However, there have been numerous reports of signal decays that are not monoexponential, particularly in the white matter. Theory We modeled diffusion in neural tissue from the perspective of the continuous time random walk. The characteristic diffusion decay is represented by the Mittag-Leffler function, which relaxes a priori assumptions about the governing statistics. We then used entropy as a measure of the anomalous features for the characteristic function. Methods Diffusion-weighted MRI experiments were performed on a fixed rat brain using an imaging spectrometer at 17.6 T with b-values arrayed up to 25,000 s/mm2. Additionally, we examined the impact of varying either the gradient strength, q, or mixing time, Δ, on the observed diffusion dynamics. Results In white and gray matter regions, the Mittag-Leffler and entropy parameters demonstrated new information regarding subdiffusion and produced different image contrast from that of the classical diffusion coefficient. The choice of weighting on q and Δ produced different image contrast within the regions of interest. Conclusion We propose these parameters have the potential as biomarkers for morphology in neural tissue.

In this high-resolution magnetic resonance imaging (MRI) study at 17.6 Tesla of a fixed rat brain, we used the continuous time random walk theory (CTRW) for Brownian motion to characterize anomalous diffusion. The complex mesoporus structure of biological tissues (membranes, organelles, and cells) perturbs the motion of the random walker (water molecules in proton MRI) introducing halts between steps (waiting times) and restrictions on step sizes (jump lengths). When such waiting times and jump lengths are scaled with probability distributions that follow simple inverse power laws (t−(1+α), |x|−(1+β)) non-Gaussian motion gives rise to sub- and super- diffusion. In the CTRW approach, the Fourier transform yields a solution to the generalized diffusion equation that can be expressed by the Mittag-Leffler function (MLF), Eα (− Dα, β|q|βΔα). We interrogated both white and gray matter regions in a 1 mm slice of a fixed rat brain (190 μm in plane resolution) with diffusion weighted MRI experiments using b-values up to 25,000 s/mm2, by independently varying q and Δ. When fitting these data to our model, the fractional order parameters, α and β, and the entropy measure, H(q,Δfalse‒), were found to provide excellent contrast between white and gray matter and to give results that were sensitive to the type of diffusion experiment performed.

Social recognition, the ability to recognize individuals that were previously encountered, requires complex integration of sensory inputs with previous experience. Here, we use a variety of approaches to discern how oxytocin-sensitive neurons in the PFC exert descending control over a circuit mediating social recognition in mice. Using male mice with Cre-recombinase directed to the oxytocin receptor gene (Oxtr), we revealed that oxytocin receptors (OXTRs) are expressed on glutamatergic neurons in the PFC, optogenetic stimulation of which elicited activation of neurons residing in several mesolimbic brain structures. Optogenetic stimulation of axons in the BLA arising from OXTR-expressing neurons in the PFC eliminated the ability to distinguish novel from familiar conspecifics, but remarkably, distinguishing between novel and familiar objects was unaffected. These results suggest that an oxytocin-sensitive PFC to BLA circuit is required for social recognition. The implication is that impaired social memory may manifest from dysregulation of this circuit.

Aim Butyrate is a major gut microbiota‐derived metabolite. Reduced butyrate‐producing bacteria has been reported in the spontaneously hypertensive rat (SHR), a model of hypertension characterized by dysfunctional autonomic nervous system and gut dysbiosis. Here, we demonstrate a potential mechanism for butyrate in blood pressure regulation. Methods High‐performance liquid chromatography and liquid chromatography‐mass spectrometry were performed to measure butyrate levels in feces and serum. Ussing chamber determined butyrate transport in colon ex vivo. Real‐time PCR and immunohistochemistry evaluated expression of butyrate transporter, Slc5a8, in the colon. Mean arterial blood pressure was measured in catheterized anesthetized rats before and after a single butyrate intracerebroventricular injection. Activity of cardioregulatory brain regions was determined by functional magnetic resonance imaging to derive neural effects of butyrate. Results In the SHR, we demonstrated elevated butyrate levels in cecal content, but diminished butyrate levels in circulation, possibly due to reduced expression of Slc5a8 transporter in the colon. In addition, we observed lower expression levels of butyrate‐sensing receptors in the hypothalamus of SHR, likely leading to the reduced effects of centrally administered butyrate on blood pressure in the SHR. Functional magnetic resonance imaging revealed reduced activation of cardioregulatory brain regions following central administration of butyrate in the SHR compared to control. Conclusion We demonstrated a reduced availability of serum butyrate in the SHR, possibly due to diminished colonic absorption. Reduced expression of butyrate‐sensing receptors in the SHR hypothalamus may explain the reduced central responsiveness to butyrate, indicating microbial butyrate may play a role in blood pressure regulation.