Cell-to-cell transmission of α-synuclein (α-syn) pathology is considered to underlie the spread of neurodegeneration in Parkinson’s disease. Previous studies have demonstrated that α-syn is secreted under physiological conditions in neuronal cell lines and primary neurons. However, the molecular mechanisms that regulate extracellular α-syn secretion remain unclear. In this study, we found that inhibition of monoamine oxidase-B (MAO-B) enzymatic activity facilitated α-syn secretion in human neuroblastoma SH-SY5Y cells. Both inhibition of MAO-B by selegiline or rasagiline and siRNA-mediated knockdown of MAO-B facilitated α-syn secretion. However, TVP-1022, the S-isomer of rasagiline that is 1,000 times less active, failed to facilitate α-syn secretion. Additionally, the MAO-B inhibition-induced increase in α-syn secretion was unaffected by brefeldin A, which inhibits endoplasmic reticulum/Golgi transport, but was blocked by probenecid and glyburide, which inhibit ATP-binding cassette (ABC) transporter functi...

Cocaine addiction is a devastating public health epidemic that continues to grow. Studies focused on identifying biological factors influencing cocaine craving and relapse vulnerability are necessary in order to promote abstinence in recovering drug users. Sex and ovarian hormones are known to influence cocaine addiction liability and relapse vulnerability in both humans and rodents. Previous studies have investigated sex differences in the time-dependent intensification or “incubation” of cue-induced cocaine craving that occurs during withdrawal from extended-access cocaine self-administration and have identified changes across the rat reproductive cycle (estrous cycle). Female rats in the estrus stage of the cycle (Estrus Females), the phase during which ovulation occurs, show an increase in the magnitude of incubated cue-induced cocaine craving compared to females in all other phases of the estrous cycle (Non-Estrus Females). Here we extend these findings by assessing incubated craving across the estrou...

Paternal stress can induce long-lasting changes in germ cells potentially propagating heritable changes across generations. To date, no studies have investigated differences in transmission patterns between stress-resilient and stress-susceptible mice. We tested the hypothesis that transcriptional alterations in sperm during chronic social defeat stress (CSDS) transmit increased susceptibility to stress phenotypes to the next generation. We demonstrate differences in offspring from stressed fathers that depend on paternal category (resilient vs susceptible) and offspring sex. Importantly, artificial insemination (AI) reveals that sperm mediates some of the behavioral phenotypes seen in offspring. Using RNA-sequencing (RNA-seq), we report substantial and distinct changes in the transcriptomic profiles of sperm following CSDS in susceptible versus resilient fathers, with alterations in long noncoding RNAs (lncRNAs) predominating especially in susceptibility. Correlation analysis revealed that these alteratio...

The sense of balance relies on vestibular hair cells, which detect head motions. Mammals have two types of vestibular hair cell, I and II, with unique morphological, molecular, and physiological properties. Furthermore, each hair cell type signals to a unique form of afferent nerve terminal. Little is known about the mechanisms in mature animals that maintain the specific features of each hair cell type or its postsynaptic innervation. We found that deletion of the transcription factor Sox2 from Type II hair cells in adult mice of both sexes caused many cells in utricles to acquire features unique to Type I hair cells and to lose Type II-specific features. This cellular transdifferentiation, which included changes in nuclear size, chromatin condensation, soma and stereocilium morphology, and marker expression, resulted in a significantly higher proportion of Type I-like hair cells in all epithelial zones. Furthermore, Sox2 deletion from Type II hair cells triggered non-cell autonomous changes in vestibular...

Although feedforward activity may suffice for recognizing objects in isolation, additional visual operations that aid object recognition might be needed for real-world scenes. One such additional operation is figure-ground segmentation, extracting the relevant features and locations of the target object while ignoring irrelevant features. In this study of 60 human participants (female and male), we show objects on backgrounds of increasing complexity to investigate whether recurrent computations are increasingly important for segmenting objects from more complex backgrounds. Three lines of evidence show that recurrent processing is critical for recognition of objects embedded in complex scenes. First, behavioral results indicated a greater reduction in performance after masking objects presented on more complex backgrounds, with the degree of impairment increasing with increasing background complexity. Second, electroencephalography (EEG) measurements showed clear differences in the evoked response potenti...

Brian J. Bondy, David B. Haimes, and Nace L. Golding (see pages [6234–6245][1]) Birds and mammals can localize sounds in the horizontal plane by comparing the time of arrival of the sound at each ear. In mammals, interaural time differences are detected by neurons in the medial superior olive (

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide. It is characterized by cognitive decline and concomitant dementia, primarily resulting from progressive degeneration of cortical and hippocampal neurons. AD is definitively diagnosed postmortem by the analysis of two

Functional magnetic resonance imaging (fMRI) is among the foremost methods for mapping human brain function but provides only an indirect measure of underlying neural activity. Recent findings suggest that the neurophysiological correlates of the fMRI blood oxygenation level-dependent (BOLD) signal might be regionally specific. We examined the neurophysiological correlates of the fMRI BOLD signal in the hippocampus and neocortex, where differences in neural architecture might result in a different relationship between the respective signals. Fifteen human neurosurgical patients (10 female, 5 male) implanted with depth electrodes performed a verbal free recall task while electrophysiological activity was recorded simultaneously from hippocampal and neocortical sites. The same patients subsequently performed a similar version of the task during a later fMRI session. Subsequent memory effects (SMEs) were computed for both imaging modalities as patterns of encoding-related brain activity predictive of later fr...

Previous research points to an association between retrieval-related activity in the medial prefrontal cortex (mPFC) and preservation of emotional information compared with co-occurring neutral information following sleep. Although the role of the mPFC in emotional memory likely begins at encoding, little research has examined how mPFC activity during encoding interacts with consolidation processes to enhance emotional memory. This issue was addressed in the present study using transcranial magnetic stimulation in conjunction with an emotional memory paradigm. Healthy young adults encoded negative and neutral scenes while undergoing concurrent TMS with a modified short intermittent theta burst stimulation (sTBS) protocol. Participants received stimulation to either the mPFC or an active control site (motor cortex) during the encoding phase. Recognition memory for scene components (objects and backgrounds) was assessed after a short delay (30 min) and a long delay [24 h (including a night of sleep)] to obta...

Learning to recognize and filter familiar, irrelevant sensory stimuli eases the computational burden on the cerebral cortex. Inhibition is a candidate mechanism in this filtration process, and oscillations in the cortical local field potential (LFP) serve as markers of the engagement of different inhibitory neurons. We show here that LFP oscillatory activity in visual cortex is profoundly altered as male and female mice learn to recognize an oriented grating stimulus—low-frequency (∼15 Hz peak) power sharply increases, whereas high-frequency (∼65 Hz peak) power decreases. These changes report recognition of the familiar pattern as they disappear when the stimulus is rotated to a novel orientation. Two-photon imaging of neuronal activity reveals that parvalbumin-expressing inhibitory neurons disengage with familiar stimuli and reactivate to novelty, whereas somatostatin-expressing inhibitory neurons show opposing activity patterns. We propose a model in which the balance of two interacting interneuron circu...