The pathophysiological features of ischemia-related blood–brain barrier (BBB) disruption are widely studied using preclinical stroke models. However, in many of these models, craniectomy is required to confirm arterial occlusion via laser Doppler flowmetry or to enable direct ligation of the cerebral artery. In the present study, mice were used to construct a distal middle cerebral artery occlusion (dMCAO) model, a preclinical stroke model that requires craniectomy to enable direct ligation of the cerebral artery, or were subjected to craniectomy alone. dMCAO but not craniectomy caused neurodegeneration and cerebral infarction, but both procedures induced an appreciable increase in BBB permeability to Evans blue dye, fluorescein, and endogenous albumin but not to 10 kDa dextran-FITC, leading to cerebral edema. Using rats, we further showed that BBB disruption induced by craniectomy with no evidence of dural tearing was comparable to that induced by craniectomy involving tearing of the dura. In conclusion, ...

Compromised endocytosis in neurons leads to synapse overgrowth and altered organization of synaptic proteins. However, the molecular players and the signaling pathways which regulate the process remain poorly understood. Here, we show that σ2-adaptin, one of the subunits of the AP2-complex, genetically interacts with Mad, Medea and Dad (components of BMP signaling) to control neuromuscular junction (NMJ) growth in Drosophila . Ultrastructural analysis of σ2-adaptin mutants show an accumulation of large vesicles and membranous structures akin to endosomes at the synapse. We found that mutations in σ2-adaptin lead to an accumulation of Tkv receptors at the presynaptic membrane. Interestingly, the level of small GTPase Rab11 was significantly reduced in the σ2-adaptin mutant synapses. However, expression of Rab11 does not restore the synaptic defects of σ2-adaptin mutations. We propose a model in which AP2 regulates Tkv internalization and endosomal recycling to control synaptic growth.

Learning and memory requires coordinated activity between different regions of the brain. Here, we studied the interaction between infralimbic medial prefrontal cortex (mPFC) and hippocampal dorsal CA1 during associative odorant discrimination learning in the mouse. We found that as the animal learns to discriminate odorants in a go-no go task, the coupling of high-frequency neural oscillations to the phase of θ oscillations (θ-referenced phase-amplitude coupling or tPAC) changes in a manner that results in divergence between rewarded and unrewarded odorant-elicited changes in the θ phase-referenced power (tPRP) for β and γ oscillations. In addition, in the proficient animal there was a decrease in the coordinated oscillatory activity between CA1 and mPFC in the presence of the unrewarded odorant. Furthermore, the changes in tPAC resulted in a marked increase in the accuracy for decoding contextual odorant identity from tPRP when the animal became proficient. Finally, we studied the role of Ca2+/calmodulin...

Severe brain metabolic dysfunction and amyloid-β accumulation are key hallmarks of Alzheimer’s disease (AD). While astrocytes contribute to both pathologic mechanisms, the role of their mitochondria, which is essential for signaling and maintenance of these processes, has been largely understudied. The current work provides the first direct evidence that the mitochondrial metabolic switch 17β-hydroxysteroid dehydrogenase type 10 (17βHSD10) is expressed and active in murine astrocytes from different brain regions. While it is known that this protein is overexpressed in the brains of AD patients, we found that 17βHSD10 is also upregulated in astrocytes exposed to amyloidogenic and ischemic stress. Importantly, such catalytic overexpression of 17βHSD10 inhibits mitochondrial respiration during increased energy demand. This observation contrasts with what has been found in neuronal and cancer model systems, which suggests astrocyte-specific mechanisms mediated by the protein. Furthermore, the catalytic upregul...

Children exposed prenatally to opioids are at an increased risk for behavioral problems and executive function deficits. The prefrontal cortex (PFC) and amygdala (AMG) regulate executive function and social behavior and are sensitive to opioids prenatally. Opioids can bind to toll-like receptor 4 (TLR4) to activate microglia, which may be developmentally important for synaptic pruning. Therefore, we tested the effects of perinatal morphine exposure on executive function and social behavior in male and female mouse offspring, along with microglial-related and synaptic-related outcomes. Dams were injected once daily subcutaneously with saline ( n  = 8) or morphine (MO; 10 mg/kg; n  = 12) throughout pregestation, gestation, and lactation until offspring were weaned on postnatal day 21 (P21). Male MO offspring had impairments in attention and accuracy in the five-choice serial reaction time task, while female MO offspring were less affected. Targeted gene expression analysis at P21 in the PFC identified altera...

Several populations of neurons are purported to degenerate in Parkinson’s disease (PD). One current hypothesis suggests that vulnerable neurons in PD share common characteristics including projecting to voluminous territories and having extremely long and branched axonal domains with large numbers of neurotransmitter release sites. In this study, we used a mouse in vitro culture system to compare the axonal domain of neuronal populations suspected to be vulnerable in PD to that of neuronal populations considered at a lesser risk. In the first category, we included dopamine (DA) neurons of the substantia nigra, noradrenergic neurons of the locus coeruleus (LC), serotonin neurons of the raphe nuclei (R), and cholinergic neurons of the dorsal motor nucleus of the vagus (DMV). In the second category, we included DA neurons of the ventral tegmental area, cholinergic neurons of the hypoglossal nucleus, and cholinergic interneurons of the dorsal striatum. Validating their differential vulnerability, we find that,...

Trafficking of transducin (Gαt) in rod photoreceptors is critical for adaptive and modulatory responses of the retina to varying light intensities. In addition to fine-tuning phototransduction gain in rod outer segments (OSs), light-induced translocation of Gαt to the rod synapse enhances rod to rod bipolar synaptic transmission. Here, we show that the rod-specific loss of Frmpd1 (FERM and PDZ domain containing 1), in the retina of both female and male mice, results in delayed return of Gαt from the synapse back to outer segments in the dark, compromising the capacity of rods to recover from light adaptation. Frmpd1 directly interacts with Gpsm2 (G-protein signaling modulator 2), and the two proteins are required for appropriate sensitization of rod-rod bipolar signaling under saturating light conditions. These studies provide insight into how the trafficking and function of Gαt is modulated to optimize the photoresponse and synaptic transmission of rod photoreceptors in a light-dependent manner.

To understand a dialogue, we need to know the topics that are being discussed. This enables us to integrate our knowledge of what was said previously to interpret the current dialogue. This study involved a large-scale behavioral experiment conducted online and a separate fMRI experiment, both testing human participants. In both, we selectively manipulated knowledge about the narrative content of dialogues presented in short videos. The clips were scenes from situation comedies that were split into two parts. The speech in the part 1 clips could either be presented normally or spectrally rotated to render it unintelligible. The part 2 clips that concluded the scenes were always presented normally. The behavioral experiment showed that knowledge of the preceding narrative boosted memory for the part 2 clips as well as increased the intersubject semantic similarity of recalled descriptions of the dialogues. The fMRI experiment replicated the finding that prior knowledge improved memory for the conclusions of...

Oscillatory activity in the human brain is dominated by posterior alpha oscillations (8–14 Hz), which have been shown to be functionally relevant in a wide variety of cognitive tasks. Although posterior alpha oscillations are commonly considered a single oscillator anchored at an individual alpha frequency (∼10 Hz), previous work suggests that individual alpha frequency reflects a spatial mixture of different brain rhythms. In this study, we assess whether independent component analysis (ICA) can disentangle functionally distinct posterior alpha rhythms in the context of visual short-term memory retention. Magnetoencephalography (MEG) was recorded in 33 subjects while performing a visual working memory task. Group analysis at sensor level suggested the existence of a single posterior alpha oscillator that increases in power and decreases in frequency during memory retention. Conversely, single-subject analysis of independent components revealed the existence of two dissociable alpha rhythms: one that incre...

Given its inputs from auditory structures and neuromodulatory systems, the posterior tail of the striatum is ideally positioned to influence behavioral responses to acoustic stimuli according to context and previous rewards. Results from previous studies indicate that neurons in this striatal region display selective responses to sounds. However, it is not clear whether different striatal cell classes code for distinct features of sounds or how different striatal output pathways may use acoustic information to guide behavior. Here we compared the sound-evoked responses of posterior striatal neurons that form the striatal direct pathway (and express the dopamine receptor D1) to the responses of neighboring neurons in naive mice. We achieved this via optogenetic photo-identification of D1-expressing neurons during extracellular electrophysiological recordings in awake head-fixed mice of both sexes. We found that the frequency tuning of sound-responsive direct-pathway striatal neurons is comparable with that ...