Omnipause neurons (OPNs) in the nucleus raphe interpositus have tonic activity while the eyes are stationary (‘fixation’), but stop firing immediately before and during saccades. To locate the suppression’s source, we analyzed synaptic inputs from the rostral and caudal superior colliculi (SCs) to OPNs by using intracellular recording and staining, and investigated pathways transmitting the inputs in anesthetized cats of both sexes. Electrophysiologically- or morphologically-identified OPNs received monosynaptic excitation from the rostral SCs with contralateral dominance, and received disynaptic inhibition from the caudal SCs with ipsilateral dominance. Cutting the tectoreticular tract transversely between the contralateral OPN and inhibitory burst neuron (IBN) regions eliminated inhibition from the caudal SCs, but not excitation from the rostral SCs in OPNs. In contrast, a midline section between IBN regions eliminated disynaptic inhibition in OPNs from the caudal SCs, but did not affect the monosynaptic...

Long-term potentiation (LTP) and long-term depression (LTD) in the spinal dorsal horn reflect activity-dependent synaptic plasticity and central sensitization in chronic pain. Tetanic high-frequency stimulation is commonly used to induce LTP in the spinal cord. However, primary afferent nerves often display low-frequency, rhythmic bursting discharges in painful conditions. Here, we determined how theta-burst stimulation (TBS) of primary afferents impacts spinal cord synaptic plasticity and nociception. We found that TBS induced more LTP, whereas tetanic stimulation induced more LTD, in mouse spinal lamina II neurons. TBS induced LTP, but not LTD, in 50% of excitatory neurons expressing vesicular glutamate transporter-2 (VGluT2). By contrast, TBS induced LTD and LTP in 12%–16% of vesicular GABA transporter (VGAT)-expressing inhibitory neurons. Nerve injury significantly increased the prevalence of TBS-induced LTP in VGluT2-expressing, but not VGAT-expressing, lamina II neurons. Blocking NMDARs, inhibiting α...

Despite being canonically considered a motor control structure, the cerebellum is increasingly recognized for important roles in processes beyond this traditional framework, including seizure suppression. Excitatory fastigial neurons project to a large number of downstream targets, and it is unclear whether this broad targeting underlies seizure suppression, or whether a specific output may be sufficient. To address this question, we used the intrahippocampal kainic acid mouse model of temporal lobe epilepsy, male and female animals, and a dual-virus approach to selectively label and manipulate fastigial outputs. We examined fastigial neurons projecting to the superior colliculus, medullary reticular formation, and central lateral nucleus of the thalamus, and found that these comprise largely nonoverlapping populations of neurons that send collaterals to unique sets of additional, somewhat overlapping, thalamic and brainstem regions. We found that neither optogenetic stimulation of superior colliculus nor ...

With the wide adoption of genomic sequencing in children having seizures, an increasing number of SCN2A genetic variants have been revealed as genetic causes of epilepsy. Voltage-gated sodium channel Nav1.2, encoded by gene SCN2A , is predominantly expressed in the pyramidal excitatory neurons and supports action potential (AP) firing. One recurrent SCN2A genetic variant is L1342P, which was identified in multiple patients with epileptic encephalopathy and intractable seizures. However, the mechanism underlying L1342P-mediated seizures and the pharmacogenetics of this variant in human neurons remain unknown. To understand the core phenotypes of the L1342P variant in human neurons, we took advantage of a reference human-induced pluripotent stem cell (hiPSC) line from a male donor, in which L1342P was introduced by CRISPR/Cas9-mediated genome editing. Using patch-clamping and microelectrode array (MEA) recordings, we revealed that cortical neurons derived from hiPSCs carrying heterozygous L1342P variant have...

Learned associations between stimuli allow us to model the world and make predictions, crucial for efficient behavior (e.g., hearing a siren, we expect to see an ambulance and quickly make way). While there are theoretical and computational frameworks for prediction, the circuit and receptor-level mechanisms are unclear. Using high-density EEG, Bayesian modeling, and machine learning, we show that inferred “causal” relationships between stimuli and frontal alpha activity account for reaction times (a proxy for predictions) on a trial-by-trial basis in an audiovisual delayed match-to-sample task which elicited predictions. Predictive β feedback activated sensory representations in advance of predicted stimuli. Low-dose ketamine, an NMDAR blocker, but not the control drug dexmedetomidine, perturbed behavioral indices of predictions, their representation in higher-order cortex, feedback to posterior cortex, and pre-activation of sensory templates in higher-order sensory cortex. This study suggests that predic...

In the article “Connecting TNF-α Signaling Pathways to iNOS Expression in a Mouse Model of Alzheimer's Disease: Relevance for the Behavioral and Synaptic Deficits Induced by Amyloid β Protein,” by Rodrigo Medeiros, Rui D. S. Prediger, Giselle F. Passos, Pablo Pandolfo, Filipe S. Duarte,

How does the brain integrate signals with different timescales to drive purposeful actions? Brain-machine interfaces (BMIs) offer a powerful tool to causally test how distributed neural networks achieve specific neural patterns. During neuroprosthetic learning, actuator movements are causally linked to primary motor cortex (M1) neurons, i.e., “direct” neurons that project to the decoder and whose firing is required to successfully perform the task. However, it is unknown how such direct M1 neurons interact with both “indirect” local (in M1 but not part of the decoder) and across area neural populations (e.g., in premotor cortex/M2), all of which are embedded in complex biological recurrent networks. Here, we trained male rats to perform a M1-BMI task and simultaneously recorded the activity of indirect neurons in both M2 and M1. We found that both M2 and M1 indirect neuron populations could be used to predict the activity of the direct neurons (i.e., “BMI-potent activity”). Interestingly, compared with M1 ...

Our eyes are constantly in motion and the various kinds of eye movements are closely linked to many aspects of human cognitive processing. Measuring all possible eye movements unobtrusively is not achievable with current methods. Video-based eye-trackers only measure rotational but not translational motion of the eye, require a calibration process relying on the participant’s self-report of accurate fixation, and do not work if vision of the eyeball is blocked. Scleral search coils attach physical weight on the eyeball and also do not measure translation. Here we describe a novel and fully automated method to use real-time Magnetic Resonance Imaging (MRI) for eye tracking. We achieved a temporal resolution sufficient to measure eye rotations and translations as short as those that occur within a blink and behind a closed eyelid. To demonstrate this method we measured the full extent of the blink-related eye movement for two individuals, suggesting that the eye approaches a holding position during lid closu...

A metanalysis identified Regulator of G protein Signaling 6 ( RGS6 ) as one of 23 loci with pleiotropic effects on four or more human psychiatric disorders. This finding is significant as it confirms/extends the findings of numerous other studies implicating RGS6 in CNS function and pathology. RGS6 is a highly conserved member of the RGS protein family whose cellular roles are likely affected by mRNA splicing and alternative domain inclusion/exclusion. Indeed, we previously identified multiple RGS6 splice variants predicted to produce 36 distinct protein isoforms containing either long (RGS6L) or short (RGS6S) N-terminal domains, an incomplete or intact GGL domain, and 9 alternative C-termini. Unfortunately, sequence similarities between the isoforms have made it difficult to confirm their individual existence and/or to determine their unique functions. Here, we developed 3 RGS6-specific antibodies that recognize all RGS6 protein isoforms (RGS6-fl), the N-terminus of RGS6L isoforms (RGS6-L), and an 18 amin...