Activity-dependent insertion of the tropomyosin-related kinase B (TrkB) receptor into the plasma membrane can explain, in part, the preferential effect of brain-derived neurotrophic factor (BDNF) on active neurons and synapses; however, the underlying molecular mechanisms remain obscure. Here, we report a novel function for carboxypeptidase E (CPE) in controlling chemical long-term potentiation (cLTP) stimuli-induced TrkB surface delivery in hippocampal neurons. Total internal reflection fluorescence (TIRF) assays and line plot assays showed that CPE facilitates TrkB transport from dendritic shafts to the plasma membrane. The Box2 domain in the juxtamembrane region of TrkB and the C-terminus of CPE are critical for the activity-dependent plasma membrane insertion of TrkB. Moreover, TAT-CPE452-466, which could block the association between CPE and TrkB, significantly inhibited neuronal activity-enhanced BDNF signaling and dendritic spine morphological plasticity in cultured hippocampal neurons. Microinfusio...

Structural plasticity of dendritic spines is considered to be an important basis of synaptic plasticity, learning and memory. Here, we induced input-specific structural LTP (sLTP) in single dendritic spines in organotypic hippocampal slices from mice of either sex and performed ultrastructural analyses of the spines using efficient correlative light and electron microscopy (CLEM). We observed reorganization of the PSD nanostructure, such as perforation and segmentation, at 2-3, 20, and 120 min after sLTP induction. In addition, PSD and nonsynaptic axon-spine interface (nsASI) membrane expanded unevenly during sLTP. Specifically, the PSD area showed a rapid increase at 2-3 min after sLTP induction. The PSD growth was to a degree less than spine volume growth at 2-3 min and 20 min after sLTP induction but became similar at 120 min. On the other hand, the nsASI area showed a profound and lasting expansion, to a degree similar to spine volume growth throughout the process. These rapid ultrastructural changes i...

Evidence from animal and human research shows that established memories can undergo changes after reactivation through a process called reconsolidation. Alterations of the level of the stress hormone cortisol may provide a way to manipulate reconsolidation in humans. Here, in a double-blind, within-subject design, we reactivated a 3-day-old memory at 3:55 a.m. in sixteen men and four women, immediately followed by oral administration of metyrapone vs. placebo, to examine whether metyrapone-induced suppression of the morning cortisol rise may influence reconsolidation processes during and after early morning sleep. Crucially, reactivation followed by cortisol suppression vs. placebo resulted in enhanced memory for the reactivated episode tested four days after reactivation. This enhancement after cortisol suppression was specific for the reactivated episode vs. a non-reactivated episode. These findings suggest that when reactivation of memories is immediately followed by suppression of cortisol levels durin...

Radial glial progenitor cells (RGCs) in the dorsal telencephalon directly or indirectly produce excitatory projection neurons and macroglia of the neocortex. Recent evidence shows that the pool of RGCs is more heterogeneous than originally thought and that progenitor subpopulations can generate particular neuronal cell types. Using single cell RNA sequencing, we have studied gene expression patterns of RGCs with different neurogenic behavior at early stages of cortical development. At this early age, some RGCs rapidly produce postmitotic neurons, whereas others self-renew and undergo neurogenic divisions at a later age. We have identified candidate genes that are differentially expressed between these early RGCs subpopulations, including the transcription factor Sox9. Using in utero electroporation in embryonic mice of either sex, we demonstrate that elevated Sox9 expression in progenitors affects RGC cell-cycle duration and leads to the generation of upper-layer cortical neurons. Our data thus reveal mole...

Hearing in noise is a problem often assumed to depend on encoding of energy level by channels tuned to target frequencies, but few studies have tested this hypothesis. The present study examined neural correlates of behavioral tone-in-noise (TIN) detection in budgerigars ( Melopsittacus undulatus ; either sex), a parakeet species with human-like behavioral sensitivity to many simple and complex sounds. Behavioral sensitivity to tones in bandlimited noise was assessed using operant-conditioning procedures. Neural recordings were made in awake animals from midbrain-level neurons in the inferior colliculus, the first processing stage of the ascending auditory pathway with pronounced rate-based encoding of stimulus amplitude modulation. Budgerigar TIN detection thresholds were similar to human thresholds across the full range of frequencies (0.5-4 kHz) and noise levels (45-85 dB SPL) tested. Also as in humans, thresholds were minimally impacted by a challenging roving-level condition with random variation in b...

The regulation of synaptic connectivity in the brain is vital to proper functioning and development of the central nervous system (CNS). Formation of neural networks in the CNS has been shown to be heavily influenced by astrocytes, which secrete factors, including thrombospondin (TSP) family proteins, that promote synaptogenesis. However, whether this process is different between males and females has not been thoroughly investigated. In this study, we found that cortical neurons purified from newborn male rats showed a significantly more robust synaptogenic response compared to female-derived cells when exposed to factors secreted from astrocytes. This difference was driven largely by the neuronal response to thrombospondin-2 (TSP2), which increased synapses in male neurons while showing no effect on female neurons. Blockade of endogenous 17β-estradiol production with letrozole normalized the TSP response between male and female cells, indicating a level of regulation by estrogen signaling. Our results su...

Approximately 5 million people die from diseases related to nicotine addiction and tobacco use each year. The nicotine-induced increase of corticomesolimbic dopaminergic (DAergic) transmission and hypodopaminergic conditions occurring during abstinence are important for maintaining drug-use habits. We examined the notion of reequilibrating DAergic transmission by inhibiting phosphodiesterase 7 (PDE7), an intracellular enzyme highly expressed in the corticomesolimbic circuitry and responsible for the degradation of cyclic adenosine monophosphate (cAMP), the main second messenger modulated by DA receptor activation. Using selective PDE7 inhibitors, we demonstrated in male rats that systemic PDE7 enzyme inhibition reduced nicotine self-administration and prevented reinstatement to nicotine seeking evoked by cues or by the pharmacological stressor yohimbine. The effect was also observed by direct application of the PDE7 inhibitors into the nucleus accumbens (NAc) shell but not into the core. Inhibition of PDE7...

Within the perinatal stroke field, there is a need to establish preclinical models where putative biomarkers for motor function can be examined. In a mouse model of perinatal stroke, we evaluated motor map size and movement latency following optogenetic cortical stimulation against three factors of post-stroke biomarker utility: (1) correlation to chronic impairment on a behavioral test battery; (2) amenability to change using a skilled motor training paradigm; and (3) ability to distinguish individuals with potential to respond well to training. Thy1-ChR2-YFP mice received a photothrombotic stroke at postnatal day 7 and were evaluated on a battery of motor tests between days 59 and 70. Following a cranial window implant, mice underwent longitudinal optogenetic motor mapping both before and after 3 weeks of skilled forelimb training. Map size and movement latency of both hemispheres were positively correlated with impaired spontaneous forelimb use, whereas only ipsilesional hemisphere map size was correlat...

The brain is highly sensitive to auditory regularities and exploits the predictable order of sounds in many situations, from parsing complex auditory scenes, to the acquisition of language. To understand the impact of stimulus predictability on perception, it is important to determine how the detection of predictable structure influences processing and attention. Here, we use pupillometry to gain insight into the effect of sensory regularity on arousal. Pupillometry is a commonly used measure of salience and processing effort, with more perceptually salient or perceptually demanding stimuli consistently associated with larger pupil diameters. In two experiments we tracked human listeners' pupil dynamics while they listened to sequences of 50-ms tone pips of different frequencies. The order of the tone pips was either random, contained deterministic (fully predictable) regularities (experiment 1, n = 18, 11 female) or had a probabilistic regularity structure (experiment 2, n = 20, 17 female). The sequences ...

Understanding adolescent decision-making is significant for informing basic models of neurodevelopment as well as for the domains of public health and criminal justice. System-based theories posit that adolescent decision-making is guided by activity related to reward and control processes. While successful at explaining behavior, system-based theories have received inconsistent support at the neural level, perhaps because of methodological limitations. Here, we used two complementary approaches to overcome said limitations and rigorously evaluate system-based models. Using decision-level modeling of fMRI data from a risk-taking task in a sample of 2000+ decisions across 51 human adolescents (25 females, mean age = 15.00 years), we find support for system-based theories of decision-making. Neural activity in lateral PFC and a multivariate pattern of cognitive control both predicted a reduced likelihood of risk-taking, whereas increased activity in the NAcc predicted a greater likelihood of risk-taking. Int...