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 ...

Voices are arguably among the most relevant sounds in humans’ everyday life, and several studies have suggested the existence of voice-selective regions in the human brain. Despite two decades of research, defining the human brain regions supporting voice recognition remains challenging. Moreover, whether neural selectivity to voices is merely driven by acoustic properties specific to human voices (e.g., spectrogram, harmonicity), or whether it also reflects a higher-level categorization response is still under debate. Here, we objectively measured rapid automatic categorization responses to human voices with fast periodic auditory stimulation (FPAS) combined with electroencephalography (EEG). Participants were tested with stimulation sequences containing heterogeneous non-vocal sounds from different categories presented at 4 Hz (i.e., four stimuli/s), with vocal sounds appearing every three stimuli (1.333 Hz). A few minutes of stimulation are sufficient to elicit robust 1.333-Hz voice-selective focal brai...

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin ( HTT ) gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, HttQ175/+ , and from wild-type controls. We used 14- to 15-month-old male mice, a time point at which multiple behavioral, neuroanatomical, and neurophysical changes are present but at which there is no known cell death. Thousands of differentially expressed genes (DEGs) were distributed across most striatal cell types, including transcriptional changes in glial populations that are not apparent from RNA-seq of bulk tissue. Reconstruction of cell type-specific transcriptional networks...

Early-life inflammatory stress increases seizure susceptibility later in life. However, possible sex- and age-specific differences and the associated mechanisms are largely unknown. C57BL/6 mice were bred in house, and female and male pups were injected with lipopolysaccharide (LPS; 100 μg/kg, i.p.) or vehicle control (saline solution) at postnatal day 14 (P14). Seizure threshold was assessed in response to pentylenetetrazol (1% solution, i.v.) in adolescence (∼P40) and adulthood (∼P60). We found that adult, but not adolescent, mice treated with LPS displayed ∼34% lower seizure threshold compared with controls. Females and males showed similar increased seizure susceptibility, suggesting that altered brain excitability was age dependent, but not sex dependent. Whole-cell recordings revealed no differences in excitatory synaptic activity onto CA1 pyramidal neurons from control or neonatally inflamed adolescent mice of either sex. However, adult mice of both sexes previously exposed to LPS displayed spontane...

The fact that the transmission and processing of visual information in the brain takes time presents a problem for the accurate real-time localization of a moving object. One way this problem might be solved is extrapolation: using an object's past trajectory to predict its location in the present moment. Here, we investigate how a simulated in silico layered neural network might implement such extrapolation mechanisms, and how the necessary neural circuits might develop. We allowed an unsupervised hierarchical network of velocity-tuned neurons to learn its connectivity through spike-timing-dependent plasticity (STDP). We show that the temporal contingencies between the different neural populations that are activated by an object as it moves causes the receptive fields of higher-level neurons to shift in the direction opposite to their preferred direction of motion. The result is that neural populations spontaneously start to represent moving objects as being further along their trajectory than where they ...

The ability to discriminate between stimuli relies on a chain of neural operations associated with perception, memory and decision-making. Accumulating studies show learning-dependent plasticity in perception or decision-making, yet whether perceptual learning modifies mnemonic processing remains unclear. Here, we trained human participants of both sexes in an orientation discrimination task, while using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) to separately examine training-induced changes in working memory (WM) representation. fMRI decoding revealed orientation-specific neural patterns during the delay period in primary visual cortex (V1) before, but not after, training, whereas neurodisruption of V1 during the delay period led to behavioral deficits in both phases. In contrast, both fMRI decoding and disruptive effect of TMS showed that intraparietal sulcus (IPS) represented WM content after, but not before, training. These results suggest that training do...

The molecular mechanisms tuning cholinergic interneuron (CIN) activity, although crucial for striatal function and behavior, remain largely unexplored. Previous studies report that the Etv1/Er81 transcription factor is vital for regulating neuronal maturation and activity. While Er81 is known to be expressed in the striatum during development, its specific role in defining CIN properties and the resulting consequences on striatal function is unknown. We report here that Er81 is expressed in CINs and its specific ablation leads to prominent changes in their molecular, morphologic, and electrophysiological features. In particular, the lack of Er81 amplifies intrinsic delayed-rectifier and hyperpolarization-activated currents, which subsequently alters the tonic and phasic activity of CINs. We further reveal that Er81 expression is required for normal CIN pause and time-locked responses to sensorimotor inputs in awake mice. Overall, this study uncovers a new cell type-specific control of CIN function in the s...

Our subjective perception of time is optimized to temporal regularities in the environment. This is illustrated by the central tendency effect: When estimating a range of intervals, short intervals are overestimated, whereas long intervals are underestimated to reduce the overall estimation error. Most models of interval timing ascribe this effect to the weighting of the current interval with previous memory traces after the interval has been perceived. Alternatively, the perception of the duration could already be flexibly tuned to its temporal context. We investigated this hypothesis using an interval reproduction task in which human participants (both sexes) reproduced a shorter and longer interval range. As expected, reproductions were biased toward the subjective mean of each presented range. EEG analyses showed that temporal context indeed affected neural dynamics during the perception phase. Specifically, longer previous durations decreased contingent negative variation and P2 amplitude and increase...

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...