Raghavan Gopalakrishnan, David A. Cunningham, Olivia Hogue, Madeleine Schroedel, Brett A. Campbell, et al. (see pages [5186–5197][1]) Bidirectional communication between the cerebral cortex and the cerebellum is required for many brain functions. For example, motor planning and coordination are

Populations of cortical neurons generate rhythmic fluctuations in their ongoing spontaneous activity. These fluctuations can be seen in the local field potential (LFP), which reflects summed return currents from synaptic activity in the local population near a recording electrode. The LFP is spectrally broad, and many researchers view this breadth as containing many narrowband oscillatory components that may have distinct functional roles. This view is supported by the observation that the phase of narrowband oscillations is often correlated with cortical excitability and can relate to the timing of spiking activity and the fidelity of sensory evoked responses. Accordingly, researchers commonly tune in to these channels by narrowband filtering the LFP. Alternatively, neural activity may be fundamentally broadband and composed of transient, nonstationary rhythms that are difficult to approximate as oscillations. In this view, the instantaneous state of the broad ensemble relates directly to the excitability...

Dual leucine zipper kinase (DLK) plays a pivotal role in the development, degeneration, and regeneration of neurons. DLK can regulate gene expression post-transcriptionally, but the underlying mechanism remains poorly understood. The Drosophila DLK, Wallenda (Wnd) regulates the expression of Down syndrome cell adhesion molecule (Dscam) to control presynaptic arbor growth. This regulation is mediated by the 3’ untranslated region (3’UTR) of Dscam mRNA, which suggests that RNA binding proteins (RBPs) mediate DLK function. We performed a genome-wide cell-based RNAi screen of RBPs and identified the cytoplasmic poly(A)-binding protein, pAbp, as an RBP that mediates Wnd-induced increase in Dscam expression. Genetic analysis shows that Wnd requires pAbp for promoting presynaptic arbor growth and for enhancing Dscam expression. Our analysis revealed that Dscam mRNAs harbor short poly(A) tails. We identified a region in Dscam 3’UTR that specifically interacts with pAbp. Removing this region significantly reduced W...

Experiences of physical exertion guide our assessments of effort. While these assessments critically influence our decisions to engage in daily activities, little is known about how they are generated. We had female and male human participants exert grip force and assess how effortful these exertions felt; and used magnetic resonance spectroscopy (MRS) to measure their brain GABA concentration. We found variability in exertion (i.e., the coefficient of variation in their force exertion profile) was associated with increases in assessments of effort, making participants judge efforts as more costly. GABA levels in the sensorimotor cortex (SM1) moderated the influence of exertion variability on over-assessments of effort. In individuals with higher sensorimotor GABA, exertion variability had a diminished influence on over-assessments of effort. Essentially, sensorimotor GABA had a protective effect on the influence of exertion variability on inflations of effort assessment. Our findings provide a neurobiolog...

The lateral habenula (LHb) balances reward and aversion by opposing activation of brain reward nuclei and is involved the inhibition of responding for cocaine in a model of impulsive behavior. Previously, we reported that the suppression of cocaine seeking was prevented by LHb inactivation or nonselective antagonism of LHb mAChRs. Here, we investigate mAChR subtypes mediating the effects of endogenous acetylcholine in this model of impulsive drug seeking and define cellular mechanisms in which mAChRs alter LHb neuron activity. Using in vitro electrophysiology, we find that LHb neurons are depolarized or hyperpolarized by the cholinergic agonists oxotremorine-M (Oxo-M) and carbachol (CCh), and that mAChRs inhibit synaptic GABA and glutamatergic inputs to these cells similarly in male and female rats. Synaptic effects of CCh were blocked by the M2-mAChR (M2R) antagonist AFDX-116 and not by pirenzepine, an M1-mAChR (M1R) antagonist. Oxo-M-mediated depolarizing currents were also blocked by AFDX-116. Although ...

In human and non-human primates, reflexive tracking eye movements can be initiated at very short latency in response to a rapid shift of the image. Previous studies in humans have shown that only a part of the central visual field is optimal for driving ocular following responses. Herein, we have investigated spatial summation of motion information across a wide range of spatial frequencies and speeds of drifting gratings by recording short-latency ocular following responses in macaque monkeys. We show that optimal stimulus size for driving ocular responses cover a small (<20° diameter), central part of the visual field that shrinks with higher spatial frequency. This signature of linear motion integration remains invariant with speed and temporal frequency. For low and medium spatial frequencies, we found a strong suppressive influence from surround motion, evidenced by a decrease of response amplitude for stimulus sizes larger than optimal. Such suppression disappears with gratings at high frequencies. T...

The orbitofrontal (OFC) and piriform (Pir) cortex play a role in fentanyl relapse after food choice-induced voluntary abstinence, a procedure mimicking abstinence due to availability of alternative non-drug rewards. We used in situ hybridization and pharmacology to determine the role of OFC and Pir cannabinoid and dopamine receptors in fentanyl relapse. We trained male and female rats to self-administer food pellets for 6 days (6-h/day) and intravenous fentanyl (2.5 µg/kg/infusion) for 12 days (6-h/day). We assessed fentanyl relapse after 12 discrete choice sessions between fentanyl and food (20 trials/day), in which rats voluntarily reduced fentanyl self-administration. We used RNAscope to determine if fentanyl relapse is associated with activity (indicated by Fos ) in OFC and Pir cells expressing Cnr1 (which encodes CB1 receptors) or Drd1 and Drd2 (which encode dopamine D1 and D2 receptors). We injected a CB1 receptor antagonist or agonist (0.3 or 1.0 µg AM251 or WIN55,212-2/hemisphere) into OFC or a do...

It is well known that hippocampal place cells have spatio-temporal properties, namely that they generally respond to a single spatial location of a small environment, and they also display the temporal response property of theta phase precession, namely that the phase of spiking relative to the theta wave shifts from the late phase to early phase as the animal crosses the place field. Grid cells in layer II of the medial entorhinal cortex (MEC) also have spatio-temporal properties similar to hippocampal place cells, except that grid cells respond to multiple spatial locations that form a hexagonal pattern. Because the entorhinal cortex (EC) is the upstream area that projects strongly to the hippocampus, a number of EC-hippocampus learning models have been proposed to explain how the spatial receptive field properties of place cells emerge via synaptic plasticity. However, the question of how the phase precession properties of place cells and grid cells are related has remained unclear. This study shows how...

Altered amygdala development is implicated in the neurobiology of autism, but little is known about the coordinated development of the brain regions directly connected with the amygdala. Here we investigated the volumetric development of an amygdala-connected network, defined as the set of brain regions with monosynaptic connections with the amygdala, in autism from early to middle childhood. Nine-hundred and fifty longitudinal structural MRI scans were acquired from 282 children (93 female) with autism and 128 children with typical development (61 female) at up to four timepoints (mean ages: 39, 52, 64, 137 months, respectively). Volumes from 32 amygdala-connected brain regions were examined using mixed effects multivariate distance matrix regression. The Social Responsiveness Scale-2 was administered to assess degree of autistic traits and social impairments. The amygdala-connected network exhibited persistent diagnostic differences ( ps ≤ 0.03) that increased over time ( p s ≤ 0.02). These differences w...

Alzheimer’s disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. Ras GTPase is closely related to the synaptic function and memory. This study was to investigate the effects of farnesyl transferase inhibitor lonafarnib on the synaptic structure and function in AD male mice and explore the potential mechanism. Our results showed 50 mg/kg lonafarnib (intraperitoneal) rescued the impaired spatial memory and improved the damaged synaptic transmission and plasticity of Aβ1-42 mice. In addition, lonafarnib ameliorated the morphology of synaptic dendrites and spines in Aβ1-42 mice. Furthermore, lonafarnib enhanced α7nAChR cell surface expression and phosphorylation of downstream Akt and CaMKII in Aβ1-42 mice, which were inhibited by α7nAChR antagonist methyl lycaconitine (MLA), and increased the phosphorylation of CREB in a CaMKII- but not ERK-dependent way. Lonafarnib enhanced hippocampal brain-der...