White matter microstructure alterations in systemic lupus erythematosus: A preliminary coordinate-based meta-analysis of diffusion tensor imaging studies

Background Systemic lupus erythematosus is often accompanied with neuropsychiatric symptoms. Neuroimaging evidence indicated that microstructural white matter (WM) abnormalities play role in the neuropathological mechanism. Diffusion tensor imaging (DTI) studies allows the assessment of the microstructural integrity of WM tracts, but existing findings were inconsistent. This present study aimed to conduct a coordinate‐based meta‐analysis (CBMA) to identify statistical consensus of DTI studies in SLE. Methods Relevant studies that reported the differences of fractional anisotropy (FA) between SLE patients and healthy controls (HC) were searched systematically. Only studies reported the results in Talairach or Montreal Neurological Institute (MNI) coordinates were included. The anisotropic effect size version of signed differential mapping (AES-SDM) was applied to detect WM alterations in SLE. Results Totally, five studies with seven datasets which included 126 patients and 161 HC were identified. The pooled meta-analysis demonstrated that SLE patients exhibited significant FA reduction in the left striatum and bilateral inferior network, mainly comprised the corpus callosum (CC), bilateral inferior fronto-occipital fasciculus (IFOF), bilateral anterior thalamic projections, bilateral superior longitudinal fasciculus (SLF), left inferior longitudinal fasciculus (ILF), and left insula. No region with higher FA was identified. Conclusions Disorders of the immune system might lead to subtle WM microstructural alterations in SLE, which might be related with cognitive deficits or emotional distress symptoms. This provides a better understanding of the pathological mechanism of microstructural brain abnormalities in SLE.

Organization of cortical and thalamic input to inhibitory neurons in mouse motor cortex

Understanding how feedforward inhibition regulates movement requires knowing how cortical and thalamic projections connect to inhibitory interneurons in primary motor cortex (M1). We quantified excitatory synaptic input from sensory cortex and thalamus onto two main classes of M1 inhibitory interneurons across all cortical layers: parvalbumin (PV) expressing fast-spiking cells and somatostatin (SOM) expressing low-threshold-spiking cells. Each projection innervated M1 interneurons with a unique laminar profile. While pyramidal neurons were excited by these cortical and thalamic inputs in the same layers, different interneuron types were excited in a distinct, complementary manner, suggesting feedforward inhibition from different inputs proceeds selectively via distinct circuits. Specifically, somatosensory cortex (S1) inputs primarily targeted PV+ neurons in upper layers (L2/3) but SOM+ neurons in middle layers (L5). Somatosensory thalamus (PO) inputs primarily targeted PV+ neurons in middle layers (L5). Our results show that long-range excitatory inputs target inhibitory neurons in a cell type-specific manner which contrasts with input to neighboring pyramidal cells. In contrast to feedforward inhibition providing generic inhibitory tone in cortex, circuits are selectively organized to recruit inhibition matched to incoming excitatory circuits.

Thalamocortical axons regulate neurogenesis and laminar fates in early sensory cortex

Area-specific axonal projections from the mammalian thalamus shape unique cellular organization in target areas in the adult neocortex. How these axons control neurogenesis and early neuronal fate specification is poorly understood. By using mutant mice lacking the majority of thalamocortical axons, we show that these axons increase the number of layer 4 neurons in primary sensory areas by enhancing neurogenesis and shifting the fate of superficial layer neurons to that of layer 4 by the neonatal stage. Part of these area-specific roles are played by the thalamus-derived molecule, VGF. Our work reveals that extrinsic cues from sensory thalamic projections have an early role in the formation of cortical cytoarchitecture by enhancing the production and specification of layer 4 neurons.

Paired feed-forward excitation with delayed inhibition allows high frequency computations across brain regions

The transmission of high-frequency temporal information across brain regions is critical to perception, but the mechanisms underlying such transmission remain unclear. Long-range projection patterns across brain areas are often comprised of paired feedforward excitation followed closely by delayed inhibition, including the thalamic triad synapse, thalamic projections to cortex, and projections within hippocampus. Previous studies have shown that these joint projections produce a shortened period of depolarization, sharpening the timing window over which the postsynaptic neuron can fire. Here we show that these projections can facilitate the transmission of high-frequency computations even at frequencies that are highly filtered by neuronal membranes. Further, they can coordinate computations across multiple brain areas, even amid ongoing local activity. We suggest that paired feedforward excitation and inhibition provides a hybrid signal - carrying both a value and a clock-like trigger - to allow circuits to be responsive to input whenever it arrives.

Thalamic projections to the subthalamic nucleus contribute to movement initiation and rescue of parkinsonian symptoms

The parafascicular nucleus (Pf) of the thalamus provides major projections to the basal ganglia, a set of subcortical nuclei involved in action initiation. Here, we show that Pf projections to the subthalamic nucleus (STN), but not to the striatum, are responsible for movement initiation. Because the STN is a major target of deep brain stimulation treatments for Parkinson’s disease, we tested the effect of selective stimulation of Pf-STN projections in a mouse model of PD. Bilateral dopamine depletion with 6-OHDA created complete akinesia in mice, but Pf-STN stimulation immediately and markedly restored a variety of natural behaviors. Our results therefore revealed a functionally novel neural pathway for the initiation of movements that can be recruited to rescue movement deficits after dopamine depletion. They not only shed light on the clinical efficacy of conventional STN DBS but also suggest more selective and improved stimulation strategies for the treatment of parkinsonian symptoms.

Long-range GABAergic projections contribute to cortical feedback control of sensory processing

In sensory systems, cortical areas send excitatory projections back to subcortical areas to dynamically adjust sensory processing. Here, we uncover for the first time the existence of a cortical inhibitory feedback to subcortical sensory areas. Investigating the olfactory system, we reveal that a subpopulation of GABAergic neurons in the anterior olfactory cortex target the olfactory bulb. Analogous inhibitory cortico-thalamic projections were also present in the somatosensory system. Long-range inhibitory inputs synapsed with both local and output neurons of the olfactory bulb. At the functional level, optogenetic activation of cortical GABAergic projections caused a net subtractive inhibition of both spontaneous and odor-evoked activity in local as well as output projection neurons, mitral and tufted cells. In tufted cells, but not mitral cells, this resulted in an enhanced separation of population odor responses. Furthermore, GABAergic corticofugal projections entrained network oscillations in the communication band between the cortex and the olfactory bulb. Targeted pharmacogenetic silencing of the cortical GABAergic outputs in the olfactory bulb impaired discrimination of similar odor mixtures. Thus, cortical GABAergic feedback represents a new circuit motif in sensory systems involved in refining sensory processing and perception.

Blink Synchronized Brain Activation: Association With Ascending Arousal Network

Eye-blinking has been implicated in arousal and attention. Here we test the hypothesis that, blinking-moments represent arousal transitions associated with activation of the ascending arousal network (AAN) and its thalamic projections. For this purpose, we explored the temporal relationship between eye-blinks and fMRI BOLD activity in the AAN and thalamus during a choice-reward task and an eyes-open resting state. We show that during the task, blinks were associated with activation of AAN and thalamic nuclei at the blink moment. During rest, peaks of AAN and thalamic nuclei were not synchronized and appeared weaker except for the ventral tegmental area (VTA). Our findings of an association between eye blinks and activation of the AAN and thalamus provides strong evidence in support of the role of eye blinking in arousal transitions that are influenced by cognitive states. It also corroborates the involvement of the dopaminergic VTA nucleus in eye blinking.

Abstract 177: Brain-Wide Circuit Dynamics of Post-Stroke Recovery After Optogenetic Stimulation

Background: Post-stroke optogenetic stimulations have been shown to promote functional recovery. However, the cellular and circuit mechanisms underlying such recovery remain unclear. Elucidating key neural circuits in post-stroke recovery will be invaluable for translation of neuromodulation for stroke. Here we used optogenetic functional magnetic response imaging (ofMRI) to examine brain-wide circuit dynamics induced by optogenetic stimulation treatment (OST). Method: Male mice expressing channelrhodopsin (ChR2) in ipsilesional M1 (iM1) layer V excitatory neurons were used. ofMRI were performed on pre-stroke and post-stroke days (PD) 3, 15 and 29. OST were given daily from PD5-15. Sensorimotor tests were conducted one day prior to each ofMRI session. Mice underwent transient middle cerebral artery occlusion (intraluminal suture model, 30 minutes). Two groups were assigned: stim group (mice with 10 days of OST, n=9) and no stim group (mice without OST, n=9). Activation maps were compared between stim and no stim groups to reveal key brain circuits recovered by OST. The expression of plasticity marker GAP43 was examined using western blot. Result: Our results show that 1) Optogenetic excitatory neuronal stimulations in iM1 promotes motor function at PD 14 (P<0.01). 2) At pre-stroke, iM1 stimulations activate expected network including ipsilesional M1, M2, S1, striatum, thalamus, contralateral M1 and cerebellum. 3) At PD3, all mice exhibit a depressed response throughout the brain. 4) At PD15, ipsilesional thalamus and S1 circuits are significantly recovered by OST. Moreover, restoration of thalamic activation is correlated with behavioral recovery in the stim group. 5) At PD15, stimulated mice exhibited higher level of plasticity marker (GAP43) in the ipsilesional thalamus (P<0.05). 6) At PD29, iS1 activation remains stronger in the stim group when compared to no stim group. Conclusion: Our findings revealed key circuits underlying stimulation-induced post-stroke recovery. We found that restoration of cortico-thalamic projections is important in stimulation-induced recovery at early phase post-stroke, while sustained strengthening of ipsilesional cortico-cortical connections may be critical in the later phase of recovery.