The Timing of Sensory-Guided Behavioral Response is Represented in the Mouse Primary Somatosensory Cortex.

Whisker-guided decision making in mice is thought to critically depend on information processing occurring in the primary somatosensory cortex. However, it is not clear if neuronal activity in this "early" sensory region contains information about the timing and speed of motor response. To address this question we designed a new task in which freely moving mice learned to associate a whisker stimulus to reward delivery. The task was tailored in such a way that a wide range of delays between whisker stimulation and reward collection were observed due to differences of motivation and perception. After training, mice were anesthetized and neuronal responses evoked by stimulating trained and untrained whiskers were recorded across several cortical columns of barrel cortex. We found a strong correlation between the delay of the mouse behavioral response and the timing of multiunit activity evoked by the trained whisker, outside its principal cortical column, in layers 4 and 5A but not in layer 2/3. Circuit mapping ex vivo revealed this effect was associated with a weakening of layer 4 to layer 2/3 projection. We conclude that the processes controlling the propagation of key sensory inputs to naive cortical columns and the timing of sensory-guided action are linked.

Exposure to sublethal doses of insecticide and their effects on insects at cellular and physiological levels.

Insecticides were used as pest management tools for a long time. The appearance of resistant insects has led the scientific community to rethink their use and to study the mechanisms underlying the resistance in order to circumvent it. However, we know now that sublethal doses of insecticide induce many effects which should be taken into account for pest control. In this review, we summarized current knowledge on mechanisms used by insects to deal with exposure to sublethal dose of insecticides. Physiological and cellular changes could contribute to the adaptation of the insect to its environment making the challenge of managing pests difficult.

Stress-induced strain and brain region-specific activation of LINE-1 transposons in adult mice.

Transposable elements (TEs) are conserved mobile genetic elements that are highly abundant in most eukaryotic genomes. Although the exact function of TEs is still largely unknown, it is increasingly clear that they are significantly modulated in response to stress in a wide range of organisms, either directly or indirectly through regulation of epigenetic silencing. We investigated the effect of repeated restraint stress (2 h a day, for 5 d) on transcription levels of LINE-1 (L1) retrotransposon in the brain of inbred BALB/c, DBA/2, C57BL/6N, and outbred CD1 mice. Repeated restraint stress induced strain and brain region-specific modulation of L1 activity. We observed a significant derepression of L1 transcription in the hippocampus (HIPP) of BALB/c mice and a significant downregulation in the hippocampus of C57BL/6N mice. No significant change in L1 expression was found in the other strains and brain regions. These findings indicate in mice the control of transposons expression as an additional mechanism in stress-induced pathophysiological responses, demonstrating that their regulation is highly dependent on the strain genetic background and the brain region. Lay summary Hippocampal expression of the transposon L1 is significantly altered by repeated restraint stress in mice. L1 modulation is not only region specific, but also strain dependent, suggesting that the genetic background is an important determinant of L1 response to environmental stimuli.

Changes in SK channel expression in the basal ganglia after partial nigrostriatal dopamine lesions in rats: Functional consequences.

Parkinson's disease (PD) is a progressive neurodegenerative disease originating from the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNC). The small-conductance calcium-activated potassium (SK) channels play an essential role in the regulation of midbrain DA neuron activity patterns, as well as excitability of other types of neurons of the basal ganglia. We therefore questioned whether the SK channel expression in the basal ganglia is modified in parkinsonian rats and how this could impact behavioral performance in a reaction time task. We used a rat model of early PD in which the progressive nigrostriatal DA degeneration was produced by bilateral infusions of 6-hydroxydopamine (6-OHDA) into the striatum. In situ hybridization of SK2 and SK3 mRNA and binding of iodinated apamin (SK2/SK3 blocker) were performed at 1, 8 or 21 days postsurgery in sham and 6-OHDA lesion groups. A significant decrease of SK3 channel expression was found in the SNC of lesioned animals at the three time points, with no change of SK2 channel expression. Interestingly, an upregulation of SK2 mRNA and apamin binding was found in the subthalamic nucleus (STN) at 21 days postlesion. These results were confirmed using quantitative real time polymerase chain reaction (qRT-PCR) approach. Functionally, the local infusion of apamin into the STN of parkinsonian rats enhanced the akinetic deficits produced by nigrostriatal DA lesions in a reaction time task while apamin infusion into the SNC had an opposite effect. These effects disappear when the positive modulator of SK channels (CyPPA) is co-administered with apamin. These findings suggest that an upregulation of SK2 channels in the STN may underlie the physiological adjustment to increased subthalamic excitability following partial DA denervation.

Involvement of Striatal Cholinergic Interneurons and M1 and M4 Muscarinic Receptors in Motor Symptoms of Parkinson's Disease.

UNLABELLED: Over the last decade, striatal cholinergic interneurons (ChIs) have reemerged as key actors in the pathophysiology of basal-ganglia-related movement disorders. However, the mechanisms involved are still unclear. In this study, we address the role of ChI activity in the expression of parkinsonian-like motor deficits in a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion model using optogenetic and pharmacological approaches. Dorsal striatal photoinhibition of ChIs in lesioned ChAT(cre/cre) mice expressing halorhodopsin in ChIs reduces akinesia, bradykinesia, and sensorimotor neglect. Muscarinic acetylcholine receptor (mAChR) blockade by scopolamine produces similar anti-parkinsonian effects. To decipher which of the mAChR subtypes provides these beneficial effects, systemic and intrastriatal administration of the selective M1 and M4 mAChR antagonists telenzepine and tropicamide, respectively, were tested in the same model of Parkinson's disease. The two compounds alleviate 6-OHDA lesion-induced motor deficits. Telenzepine produces its beneficial effects by blocking postsynaptic M1 mAChRs expressed on medium spiny neurons (MSNs) at the origin of the indirect striatopallidal and direct striatonigral pathways. The anti-parkinsonian effects of tropicamide were almost completely abolished in mutant lesioned mice that lack M4 mAChRs specifically in dopamine D1-receptor-expressing neurons, suggesting that postsynaptic M4 mAChRs expressed on direct MSNs mediate the antiakinetic action of tropicamide. The present results show that altered cholinergic transmission via M1 and M4 mAChRs of the dorsal striatum plays a pivotal role in the occurrence of motor symptoms in Parkinson's disease. SIGNIFICANCE STATEMENT: The striatum, where dopaminergic and cholinergic systems interact, is the pivotal structure of basal ganglia involved in pathophysiological changes underlying Parkinson's disease. Here, using optogenetic and pharmacological approaches, we investigated the involvement of striatal cholinergic interneurons (ChIs) and muscarinic receptor subtypes (mAChRs) in the occurrence of a wide range of motor deficits such as akinesia, bradykinesia, motor coordination, and sensorimotor neglect after unilateral nigrostriatal 6-hydroxydopamine lesion in mice. Our results show that photoinhibition of ChIs in the dorsal striatum and pharmacological blockade of muscarinic receptors, specifically postsynaptic M1 and M4 mAChRs, alleviate lesion-induced motor deficits. The present study points to these receptor subtypes as potential targets for the symptomatic treatment of parkinsonian-like motor symptoms.

Striatal Cholinergic Interneurons Control Motor Behavior and Basal Ganglia Function in Experimental Parkinsonism.

Despite evidence showing that anticholinergic drugs are of clinical relevance in Parkinson's disease (PD), the causal role of striatal cholinergic interneurons (CINs) in PD pathophysiology remains elusive. Here, we show that optogenetic inhibition of CINs alleviates motor deficits in PD mouse models, providing direct demonstration for their implication in parkinsonian motor dysfunctions. As neural correlates, CIN inhibition in parkinsonian mice differentially impacts the excitability of striatal D1 and D2 medium spiny neurons, normalizes pathological bursting activity in the main basal ganglia output structure, and increases the functional weight of the direct striatonigral pathway in cortical information processing. By contrast, CIN inhibition in non-lesioned mice does not affect locomotor activity, equally modulates medium spiny neuron excitability, and does not modify spontaneous or cortically driven activity in the basal ganglia output, suggesting that the role of these interneurons in motor function is highly dependent on dopamine tone.

Acute stress alters amygdala microRNA miR-135a and miR-124 expression: inferences for corticosteroid dependent stress response.

The amygdala is a brain structure considered a key node for the regulation of neuroendocrine stress response. Stress-induced response in amygdala is accomplished through neurotransmitter activation and an alteration of gene expression. MicroRNAs (miRNAs) are important regulators of gene expression in the nervous system and are very well suited effectors of stress response for their ability to reversibly silence specific mRNAs. In order to study how acute stress affects miRNAs expression in amygdala we analyzed the miRNA profile after two hours of mouse restraint, by microarray analysis and reverse transcription real time PCR. We found that miR-135a and miR-124 were negatively regulated. Among in silico predicted targets we identified the mineralocorticoid receptor (MR) as a target of both miR-135a and miR-124. Luciferase experiments and endogenous protein expression analysis upon miRNA upregulation and inhibition allowed us to demonstrate that mir-135a and mir-124 are able to negatively affect the expression of the MR. The increased levels of the amygdala MR protein after two hours of restraint, that we analyzed by western blot, negatively correlate with miR-135a and miR-124 expression. These findings point to a role of miR-135a and miR-124 in acute stress as regulators of the MR, an important effector of early stress response.

Distinct roles of medial and lateral entorhinal cortex in spatial cognition.

It is known that the entorhinal cortex plays a crucial role in spatial cognition in rodents. Neuroanatomical and electrophysiological data suggest that there is a functional distinction between 2 subregions within the entorhinal cortex, the medial entorhinal cortex (MEC), and the lateral entorhinal cortex (LEC). Rats with MEC or LEC lesions were trained in 2 navigation tasks requiring allothetic (water maze task) or idiothetic (path integration) information processing and 2-object exploration tasks allowing testing of spatial and nonspatial processing of intramaze objects. MEC lesions mildly affected place navigation in the water maze and produced a path integration deficit. They also altered the processing of spatial information in both exploration tasks while sparing the processing of nonspatial information. LEC lesions did not affect navigation abilities in both the water maze and the path integration tasks. They altered spatial and nonspatial processing in the object exploration task but not in the one-trial recognition task. Overall, these results indicate that the MEC is important for spatial processing and path integration. The LEC has some influence on both spatial and nonspatial processes, suggesting that the 2 kinds of information interact at the level of the EC.