1These authors contributed equally to this work.Abbreviations used: AP-1, activator protein-1; AY, acute yoke; CPu, caudate-putamen; CSA, cocaine self-administration; CY, chronic yoke; IP, intraperitoneal; IV, intravenous; NAc, nucleus accumbens; TTBS, Tris/Tween-buffered saline solution; WD, withdrawal. AbstractChronic drug exposure induces alterations in gene expression profiles that are thought to underlie the development of drug addiction. The present study examined regulation of the Fosfamily of transcription factors, specifically cFos, FosB, and DFosB, in striatal subregions during and after chronic intravenous cocaine administration in self-administering and yoked rats. We found that cFos, FosB, and DFosB exhibit regionally and temporally distinct expression patterns, with greater accumulation of DFosB protein in the nucleus accumbens (NAc) shell and core after chronic cocaine administration, whereas DFosB increases in the caudate-putamen (CPu) remained similar with either acute or chronic administration. In contrast, tolerance developed to cocaine-induced mRNA for DFosB in all three striatal subregions with chronic administration. Tolerance also developed to FosB expression, most notably in the NAc shell and CPu. Interestingly, tolerance to cocaine-induced cFos induction was dependent on volitional control of cocaine intake in ventral but not dorsal striatal regions, whereas regulation of FosB and DFosB was similar in cocaine self-administering and yoked animals. Thus, DFosBmediated neuroadaptations in the CPu may occur earlier than previously thought with the initiation of intravenous cocaine use and, together with greater accumulation of DFosB in the NAc, could contribute to addiction-related increases in cocaine-seeking behavior.

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In severe traumatic brain injury (TBI), contusions often are worsened by contusion expansion or hemorrhagic progression of contusion (HPC), which may double the original contusion volume and worsen outcome. In humans and rodents with contusion-TBI, sulfonylurea receptor 1 (SUR1) is upregulated in microvessels and astrocytes, and in rodent models, blockade of SUR1 with glibenclamide reduces HPC. SUR1 does not function by itself, but must co-assemble with either KIR6.2 or transient receptor potential cation channel subfamily M member 4 (TRPM4) to form K (SUR1-KIR6.2) or SUR1-TRPM4 channels, with the two having opposite effects on membrane potential. Both KIR6.2 and TRPM4 are reportedly upregulated in TBI, especially in astrocytes, but the identity and function of SUR1-regulated channels post-TBI is unknown. Here, we analyzed human and rat brain tissues after contusion-TBI to characterize SUR1, TRPM4, and KIR6.2 expression, and in the rat model, to examine the effects on HPC of inhibiting expression of the three subunits using intravenous antisense oligodeoxynucleotides (AS-ODN). Glial fibrillary acidic protein (GFAP) immunoreactivity was used to operationally define core versus penumbral tissues. In humans and rats, GFAP-negative core tissues contained microvessels that expressed SUR1 and TRPM4, whereas GFAP-positive penumbral tissues contained astrocytes that expressed all three subunits. Förster resonance energy transfer imaging demonstrated SUR1-TRPM4 heteromers in endothelium, and SUR1-TRPM4 and SUR1-KIR6.2 heteromers in astrocytes. In rats, glibenclamide as well as AS-ODN targeting SUR1 and TRPM4, but not KIR6.2, reduced HPC at 24 h post-TBI. Our findings demonstrate upregulation of SUR1-TRPM4 and K after contusion-TBI, identify SUR1-TRPM4 as the primary molecular mechanism that accounts for HPC, and indicate that SUR1-TRPM4 is a crucial target of glibenclamide.

Lo FS, Akkentli F, Tsytsarev V, Erzurumlu RS. Functional significance of cortical NMDA receptors in somatosensory information processing.

The whisker system of rodents is an excellent model to study peripherally evoked neural activity in the brain. Discrete neural modules represent each whisker in the somatosensory cortex (“barrels”), thalamus (“barreloids”), and brain stem (“barrelettes”). Stimulation of a single whisker evokes neural activity sequentially in its corresponding barrelette, barreloid, and barrel. Conventional optical imaging of functional activation in the brain is limited to surface structures such as the cerebral cortex. To access subcortical structures and image sensory-evoked neural activity, we designed a needle-based optical system using gradient-index (GRIN) rod lens. We performed voltage-sensitive dye imaging (VSDi) with GRIN rod lens to visualize neural activity evoked in the thalamic barreloids by deflection of whiskers in vivo. We stimulated several whiskers together to determine the sensitivity of our approach in differentiating between different barreloid responses. We also carried out stimulation of different whiskers at different times. Finally, we used muscimol in the barrel cortex to silence the corticothalamic inputs while imaging in the thalamus. Our results show that it is possible to obtain functional maps of the sensory periphery in deep brain structures such as the thalamic barreloids. Our approach can be broadly applicable to functional imaging of other core brain structures.

The neuron-specific calcium-stimulated adenylate cyclase 1 (AC1) is important for refinement of topographic maps in the brain. AC1 is expressed at all levels of the somatosensory pathway and global or region-specific gene deletions lead to differential pattern phenotypes.

Background Brain imaging methods are continually improving. Imaging of the cerebral cortex is widely used in both animal experiments and charting human brain function in health and disease. Among the animal models, the rodent cerebral cortex has been widely used because of patterned neural representation of the whiskers on the snout and relative ease of activating cortical tissue with whisker stimulation. New Method We tested a new planar solid-state oxygen sensor comprising a polymeric film with a phosphorescent oxygen-sensitive coating on the working side, to monitor dynamics of oxygen metabolism in the cerebral cortex following sensory stimulation. Results Sensory stimulation led to changes in oxygenation and deoxygenation processes of activated areas in the barrel cortex. We demonstrate the possibility of dynamic mapping of relative changes in oxygenation in live mouse brain tissue with such a sensor. Comparison with Existing Method Oxygenation-based functional magnetic resonance imaging (fMRI) is very effective method for functional brain mapping but have high costs and limited spatial resolution. Optical imaging of intrinsic signal (IOS) does not provide the required sensitivity, and voltage-sensitive dye optical imaging (VSDi) has limited applicability due to significant toxicity of the voltage-sensitive dye. Our planar solid-state oxygen sensor imaging approach circumvents these limitations, providing a simple optical contrast agent with low toxicity and rapid application. Conclusions The planar solid-state oxygen sensor described here can be used as a tool in visualization and real-time analysis of sensory-evoked neural activity in vivo. Further, this approach allows visualization of local neural activity with high temporal and spatial resolution.

Rotenone is a pesticide and piscicide, wh ich causes behavioral and biochemical changes in rats that closely resemble PD sympto ms in hu mans. Rotenone is a naturally occurring ret inoid plant ext ract derived fro m the roots of certain tropical and subtropical legu me p lants and interferes with energy p roduction in the cell. Rotenone is highly lipophilic, so it can easily cross the blood brain barrier and cellular memb rane for intracellular entry.It is known that this pesticide causes superoxide release and results in decreased energy production by inhibiting electron transport chain of mitochondria fro m NADH ubiquinone reductaseand may lead to neuronal death. The object of the current research is to investigate the effect of rotenone on synaptic transmission in h ippocampus, especially on glutamatergic transmission for a b rief exposure time. For this purpose, hippocampal CA 1 pyramidal neuronal response upon low frequency stimulation of Schaffer collateral (0.1 Hz) was recorded by the patch clamp tight-seal whole cell recording technique. Different rotenone concentrations were tested on total glutamate current; it was observed that the rotenone effect on the amplitude of glutamatergic currents is dependent on its concentration. To eliminate the rotenone induced cytoplasmic effects, ATP was excluded fro m the intracellular solution in experiments. Our experimental results show that the drug acutely and dose-dependently attenuates the currents that are med iated by glutamate, v ia a direct effect on cell membrane g lutamate receptors.