A number of cellular systems work in concert to modulate nociceptive processing in the periphery, but the mechanisms that regulate neonatal nociception may be distinct compared with adults. Our previous work indicated a relationship between neonatal hypersensitivity and growth hormone (GH) signaling. Here, we explored the peripheral mechanisms by which GH modulated neonatal nociception under normal and injury conditions (incision) in male and female mice. We found that GH receptor (GHr) signaling in primary afferents maintains a tonic inhibition of peripheral hypersensitivity. After injury, a macrophage dependent displacement of injury-site GH was found to modulate neuronal transcription at least in part via serum response factor (SRF) regulation. A single GH injection into the injured hindpaw muscle effectively restored available GH signaling to neurons and prevented acute pain-like behaviors, primary afferent sensitization, and neuronal gene expression changes. GH treatment also inhibited long-term somat...

Demand theory can be applied to analyze how animal consumers change their selection of commodities in response to changes in commodity prices, given budget constraints. Previous work has shown that demand elasticities in rats differed between uncompensated budget conditions in which the budget available to be spent on the commodities (e.g., the finite number of discrete operants to “purchase” rewards in two-alternative fixed-ratio schedules) was kept constant, and compensated budget conditions in which the budget was adjusted so that consumers could potentially continue to obtain the original reward bundles. Here, we hypothesized that rat anterior cingulate cortex (ACC) was necessary to produce this budget effect on demand elasticities. We applied excitotoxic or sham lesions to ACC in rats performing an effort task in which the prices of liquid vanilla or chocolate rewards (the effort required to obtain rewards) and the budget (the total number of operants) was manipulated. When reward prices changed, and ...

Binge eating is a distressing, transdiagnostic eating disorder symptom associated with impulsivity, particularly in negative mood states. Neuroimaging studies of bulimia nervosa (BN) report reduced activity in frontostriatal regions implicated in self-regulatory control, and an influential theory posits that binge eating results from self-regulation failures under stress. However, there is no direct evidence that psychological stress impairs self-regulation in binge-eating disorders, or that any such self-regulatory deficits generalize to binge eating in underweight individuals (i.e., anorexia nervosa bingeing/purging subtype; AN-BP). We therefore determined the effect of acute stress on inhibitory control in 85 women (BN, 33 women; AN-BP, 22 women; 30 control participants). Participants underwent repeated functional MRI scanning during performance of the Stop-signal anticipation task, a validated measure of proactive (i.e., anticipation of stopping) and reactive (outright stopping) inhibition. Neural and ...

Adam J. Dourson, Zachary K. Ford, Kathryn J. Green, Carolyn E. McCrossan, Megan C. Hofmann, et al. (see pages [4410–4427][1]) The development of human somatosensory circuits occurs perinatally and can be influenced by early sensory experience. This can be problematic, especially for preterm

The hypokinetic motor symptoms of Parkinson’s disease (PD) are closely linked with a decreased motor cortical output as a consequence of elevated basal ganglia inhibition. However, whether and how the loss of dopamine alters the cellular properties of motor cortical neurons in PD remains undefined. We induced parkinsonism in adult C57BL6 mice of both sexes by injecting neurotoxin, 6-hydroxydopamine, into the medial forebrain bundle. By using ex vivo patch-clamp recording and retrograde tracing approach, we found that the intrinsic excitability of pyramidal tract neurons (PTNs) in the primary motor cortical (M1) layer 5b was greatly decreased in parkinsonism; but the intratelencephalic neurons (ITNs) were not affected. The cell-type-specific intrinsic adaptations were associated with a depolarized threshold and broadened width of action potentials in PTNs. Moreover, the loss of midbrain dopaminergic neurons impaired the capability of M1 PTNs to sustain high-frequency firing, which could underlie their abnor...

Object segmentation–the process of parsing visual scenes–is essential for object recognition and scene understanding. We investigated how responses of neurons in macaque inferior temporal (IT) cortex contribute to object segmentation under partial occlusion. Specifically, we asked whether IT responses to occluding and occluded objects are bound together as in the visual image, or linearly separable reflecting their segmentation. We recorded the activity of 121 IT neurons while animals performed a shape discrimination task under partial occlusion. We found that for a majority (60%) of neurons responses were enhanced by partial occlusion but they were only weakly shape selective for the discriminanda at all levels of occlusion. Enhancement of IT responses in these neurons depended largely on the area of occlusion, but only minimally on the color and shape of the occluding dots. In contrast to the above group of neurons, a sizable minority responded best to the unoccluded stimulus and showed strong selectivit...

Neural activity is diverse, and varies depending on brain regions and sleep/wakefulness states. However, whether astrocyte activity differs between sleep/wakefulness states, and whether there are differences in astrocyte activity among brain regions remain poorly understood. Therefore, in this study, we recorded astrocyte intracellular calcium (Ca2+) concentrations of mice during sleep/wakefulness states in the cortex, hippocampus, hypothalamus, cerebellum, and pons using fiber photometry. For this purpose, male transgenic mice expressing the genetically encoded ratiometric Ca2+ sensor YCnano50 specifically in their astrocytes were used. We demonstrated that Ca2+ levels in astrocytes substantially decrease during rapid eye movement (REM) sleep, and increase after the onset of wakefulness. In contrast, differences in Ca2+ levels during non-rapid eye movement (NREM) sleep were observed among the different brain regions, and no significant decrease was observed in the hypothalamus and pons. Further analyses f...

Neural circuitry generating locomotor rhythm and pattern is located in the spinal cord. Most spinal cord injuries (SCI) occur above the level of spinal locomotor neurons; therefore, these circuits are a target for improving motor function after SCI. Despite being relatively intact below the injury, locomotor circuitry undergoes substantial plasticity with the loss of descending control. Information regarding cell-type specific plasticity within locomotor circuits is limited. Shox2 interneurons (INs) have been linked to locomotor rhythm generation and patterning, making them a potential therapeutic target for the restoration of locomotion after SCI. The goal of the present study was to identify SCI-induced plasticity at the level of Shox2 INs in a complete thoracic transection model in adult male and female mice. Whole cell patch clamp recordings of Shox2 INs revealed minimal changes in intrinsic excitability properties after SCI. However, afferent stimulation resulted in mixed excitatory and inhibitory inp...

The dorsomedial prefrontal cortex (dmPFC) has been linked to avoidance and decision-making under conflict, key neural computations altered in anxiety disorders. However, the heterogeneity of prefrontal projections has obscured identification of specific top-down projections involved. While the dmPFC-amygdala circuit has long been implicated in controlling reflexive fear responses, recent work suggests that dmPFC-dorsomedial striatum (DMS) projections may be more important for regulating avoidance. Using fiber photometry recordings in both male and female mice during the elevated zero maze (EZM) task, we show heightened neural activity in fronto-striatal but not fronto-amygdalar projection neurons during exploration of the anxiogenic open arms. Additionally, using optogenetics, we demonstrate that this fronto-striatal projection preferentially excites postsynaptic D1 receptor-expressing neurons in the DMS and causally controls innate avoidance behavior. These results support a model for prefrontal control o...

The initiation and propagation of the action potential (AP) along an axon allows neurons to convey information rapidly and across distant sites. Although AP properties have typically been characterised at the soma and proximal axon, the propagation of APs towards distal axonal domains of mammalian CNS neurons remains limited. We used Genetically-Encoded Voltage Indicators (GEVIs) to image APs with sub-millisecond temporal resolution simultaneously at different locations along the long axons of dissociated hippocampal neurons from rat embryos of either sex. We found that APs became sharper and showed remarkable fidelity as they traveled towards distal axons, even during a high frequency train. Blocking voltage-gated potassium channels (Kv) with 4-AP resulted in an increase in AP width in all compartments, which was stronger at distal locations and exacerbated during AP trains. We conclude that the higher levels of Kv channel activity in distal axons serves to sustain AP fidelity, conveying a reliable digita...