The Role of Mediodorsal Thalamus in Temporal Differentiation of Reward-Guided Actions

The mediodorsal thalamus (MD) is a crucial component of the neural network involved in the learning and generation of goal-directed actions. A series of experiments reported here examined the contributions of MD to the temporal differentiation of reward-guided actions. In Experiment 1, we trained rats on a discrete-trial, fixed-criterion temporal differentiation task, in which only lever presses exceeding a threshold duration value were rewarded. Pre-training MD lesions impaired temporal differentiation of action duration, by increasing the dispersion of the duration distribution. Post-training MD lesions also impaired differentiation, but by reducing the average emitted press durations, thus shifting the distribution without increasing the dispersion. In Experiment 2, we trained rats to space their lever pressing above criterion inter-press-intervals in order to earn rewards. Both pre-training and post-training MD lesions impaired the differentiation of inter-press-intervals. These results show that MD plays an important role in the acquisition and expression of action differentiation

Lemniscal and Extralemniscal Compartments in the VPM of the Rat

The ventral posteromedial thalamic nucleus (VPM) of the rat contains at least two major vibrissa-representing compartments: the dorsomedial (VPMdm), which belongs to the lemniscal afferent pathway, and the ventrolateral (VPMvl), which belongs to the extralemniscal afferent pathway. Although input–output projections and functional characteristics that distinguish these two compartments were recently clarified, a comprehensive structural analysis of these compartments and the border between them was lacking. This paper addresses structural and functional relationships between the VPMdm and VPMvl. We found that the size of the VPM is almost constant across individual rats. Next, we computed a canonical map of the VPM in the oblique plane, where structural borders are best visualized. Using the canonical map, and sequential slices cut in oblique and coronal planes, we determined the border between the VPMdm and VPMvl in the standard coronal plane, and verified it with in vivo extracellular recordings. The position of the border between these two vibrissal sub-nuclei changes along the rostrocaudal extent within the VPM due to the relative sizes of these sub-nuclei at any point. The border between the VPMdm and VPMvl, which was revealed by this technique, can now be included in atlases of the rat brain and should facilitate experimental correlation of tactile functions with thalamic regions

Dorso-Lateral Frontal Cortex of the Ferret Encodes Perceptual Difficulty during VisualDiscrimination

Visual discrimination requires sensory processing followed by a perceptual decision. Despite a growing understanding of visual areas in this behavior, it is unclear what role top-down signals from prefrontal cortex play, in particular as a function of perceptual difficulty. To address this gap, we investigated how neurons in dorso-lateral frontal cortex (dl-FC) of freely-moving ferrets encode task variables in a two-alternative forced choice visual discrimination task with high- and low-contrast visual input. About two-thirds of all recorded neurons in dl-FC were modulated by at least one of the two task variables, task difficulty and target location. More neurons in dl-FC preferred the hard trials; no such preference bias was found for target location. In individual neurons, this preference for specific task types was limited to brief epochs. Finally, optogenetic stimulation confirmed the functional role of the activity in dl-FC before target touch; suppression of activity in pyramidal neurons with the ArchT silencing opsin resulted in a decrease in reaction time to touch the target but not to retrieve reward. In conclusion, dl-FC activity is differentially recruited for high perceptual difficulty in the freely-moving ferret and the resulting signal may provide top-down behavioral inhibition

Aerobic exercise improves depressive symptoms in the unilateral 6-OHDA-lesioned rat model of Parkinson\u27s disease

Aerobic exercise has been shown to have established benefits on motor function in Parkinson\u27s disease (PD). However, the impact of exercise on depressive symptoms in PD remains unclear. This study aimed to investigate the effects of regular exercise, specifically using a forced running wheel, on both motor performance and the prevalence of depression in a unilateral 6-OHDA-lesioned rat model of PD. The behavioral outcomes of exercise were assessed through the rotarod test (RT), forelimb adjusting step test (FAST), sucrose consumption test (SCT), and novelty sucrose splash test (NSST). Our data revealed evident depressive symptoms in the PD animals, characterized by reduced sucrose consumption in the SCT and diminished exploratory activity in the NSST compared to the naïve control group. Specifically, after 11 weeks of exercise, the PD exercise group demonstrated the most significant improvements in sucrose consumption in the SCT. Additionally, this group exhibited reduced immobility and increased exploratory behavior compared to the PD control group in the NSST. Furthermore, the PD exercise group displayed the greatest improvement in correcting forelimb stepping bias. Our results suggested that a regimen of running wheel exercise enhances motor abilities and mitigates the occurrence of depressive behaviors caused by 6-OHDA dopamine depletion in the PD rat model

Activation of Orexin System Stimulates CaMKII Expression

Hyperactivity of the orexin system within the paraventricular nucleus (PVN) has been shown to contribute to increased sympathetic nerve activity (SNA) and blood pressure (BP) in rodent animals. However, the underlying molecular mechanisms remain unclear. Here, we test the hypothesis that orexin system activation stimulates calcium/calmodulin-dependent kinase II (CaMKII) expression and activation, and stimulation of CaMKII expressing PVN neurons increases SNA and BP. Real-time PCR and/or western blot were carried out to test the effect of orexin-A administration on CaMKII expression in the PVN of normal Sprague Dawley (SD) rats and orexin receptor 1 (OX1R) expressing PC12 cells. Immunostaining was performed to assess OX1R cellular localization in the PVN of SD rats as well as orexin-A treatment on CaMKII activation in cultured hypothalamic neurons. In vivo sympathetic nerve recordings were employed to test the impact of optogenetic stimulation of CaMKII-expressing PVN neurons on the renal SNA (RSNA) and BP. The results showed that intracerebroventricular injection of orexin-A into the SD rat increases mRNA expression of CaMKII subunits in the PVN. In addition, Orexin-A treatment increases CaMKII expression and its phosphorylation in OX1R-expressing PC12 cells. Furthermore, Orexin-A treatment increases CaMKII activation in cultured hypothalamic neurons from neonatal SD rats. Finally, optogenetic excitation of PVN CaMKII-expressing neurons results in robust increases in RSNA and BP in SD rats. Our results suggest that increased orexin system activity activates CaMKII expression in cardiovascular relevant regions, and this may be relevant to the downstream cardiovascular effects of CaMKII

Early Development of Network Oscillations in the Ferret Visual Cortex

Abstract Although oscillations during development have been characterized in a wide range of neural systems, little is known about the interaction between these network oscillations and neuronal spiking, and the interactions among different oscillation frequencies. Here we recorded the spontaneous and visual-elicited local field potential (LFP) and multi-unit activity (MUA) in the visual cortex of freely-moving juvenile ferrets before and after eye-opening. We found that both the spontaneous and visually-elicited LFP power was increased after eye-opening, especially in higher frequency bands (>30 Hz). Spike LFP phase coupling was decreased for lower frequency bands (theta and alpha) but slightly increased for higher frequencies (high-gamma band). A similar shift towards faster frequencies also occurred for phase-amplitude coupling; with maturation, the coupling of the theta/alpha/beta band amplitude to the delta phase was decreased and the high-gamma amplitude coupling to theta/alpha phase was increased. This shift towards higher frequencies was also reflected in the visual responses; the LFP oscillation became more entrained by visual stimulation with higher frequencies (>10 Hz). Taken together, these results suggest gamma oscillation as a signature of the maturation of cortical circuitry

Structural and functional connectivity between the lateral posterior-pulvinar complex and primary visual cortex in the ferret

The role of higher-order thalamic structures in sensory processing remains poorly understood. Here, we used the ferret (Mustela putorius furo) as a novel model species for the study of the lateral posterior-pulvinar complex (LP/pulvinar) and its structural and functional connectivity with area 17 (primary visual cortex, V1). We found reciprocal anatomical connections between the lateral part of the Lateral Posterior Nucleus of the LP/pulvinar (LPl) and V1. In order to investigate the role of this feedback loop between LPl and V1 in shaping network activity, we determined the functional interactions between LPl and supragranular, granular, and infragranular layers of V1 by recording multiunit activity (MUA) and local field potential (LFP). Coherence was strongest between LPl and supragranular V1 with the most distinct peaks in the delta and alpha frequency bands. Inter-area interaction measured by spike-phase coupling identified the delta frequency band dominated by infragranular V1 and multiple frequency bands that were most pronounced in supragranular V1. This inter-area coupling was differentially modulated by full-field synthetic and naturalistic visual stimulation. We also found that visual responses in LPl were distinct from the ones in V1 in terms of their reliability. Together, our data support a model of multiple communication channels between the LPl and layers of V1 that are enabled by oscillations in different frequency bands. This demonstration of anatomical and functional connectivity between LPl and V1 in ferrets provides a roadmap for studying the interaction dynamics during behavior and a template for identifying activity dynamics of other thalamic feedback loops

Growth Pattern in Chinese Children With 5α-Reductase Type 2 Deficiency: A Retrospective Multicenter Study

Background5α-reductase type 2 deficiency (5αRD) is an autosomal recessive hereditary disease of the group of 46, XY disorders of sex development (DSD).ObjectiveTo study the growth pattern in Chinese pediatric patients with 5αRD.SubjectsData were obtained from 141 patients with 5αRD (age: 0–16 years old) who visited eight pediatric endocrine centers from January 2010 to December 2017.MethodsIn this retrospective cohort study, height, weight, and other relevant data were collected from the multicenter hospital registration database. Baseline luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), and dihydrotestosterone (DHT) after human chorionic gonadotropin (HCG) stimulation test were measured by enzyme enhanced chemiluminescence assay. Bone age (BA) was assessed using the Greulich-Pyle (G-P) atlas. Growth curve was constructed based on λ-median-coefficient of variation method (LMS).ResultsThe height standard deviation scores (HtSDS) and weight standard deviation scores (WtSDS) in 5αRD children were in the normal range as compared to normal boys. Significantly higher HtSDS was observed in patients with 5αRD who were <1 year old (t = 3.658, 2.103, P = 0.002, 0.048, respectively), and higher WtSDS in those <6 months old (t = 2.756, P = 0.012). Then HtSDS and WtSDS decreased gradually and fluctuated near the median of the same age until 13 years. WtSDS in 5αRD children from northern China were significantly higher than those from the south (Z = -2.670, P = 0.008). The variation tendency of HtSDS in Chinese 5αRDs was consistent with the trend of stimulating T. HtSDS and stimulating T in the external masculinization score (EMS) <7 group were slightly higher than those in EMS ≥ 7 group without significant difference. Additionally, the ratio of BA over chronological age (BA/CA) was significantly <1 in children with 5αRD.ConclusionChildren with 5αRD had a special growth pattern that was affected by high levels of T, while DHT played a very small role in it. Their growth accelerated at age <1 year, followed by slowing growth and fluctuating height near normal median boys’ height. The BA was delayed in 5αRD children. Androgen treatment, which may be considered anyway for male 5αRD patients with a micropenis, may also be beneficial for growth

Parallel Thalamic Pathways for Whisking and Touch Signals in the Rat

In active sensation, sensory information is acquired via movements of sensory organs; rats move their whiskers repetitively to scan the environment, thus detecting, localizing, and identifying objects. Sensory information, in turn, affects future motor movements. How this motor-sensory-motor functional loop is implemented across anatomical loops of the whisker system is not yet known. While inducing artificial whisking in anesthetized rats, we recorded the activity of individual neurons from three thalamic nuclei of the whisker system, each belonging to a different major afferent pathway: paralemniscal, extralemniscal (a recently discovered pathway), or lemniscal. We found that different sensory signals related to active touch are conveyed separately via the thalamus by these three parallel afferent pathways. The paralemniscal pathway conveys sensor motion (whisking) signals, the extralemniscal conveys contact (touch) signals, and the lemniscal pathway conveys combined whisking–touch signals. This functional segregation of anatomical pathways raises the possibility that different sensory-motor processes, such as those related to motion control, object localization, and object identification, are implemented along different motor-sensory-motor loops

Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism

Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4–22 (Δe4–22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4–22−/− mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs