Pathological tau modifications are characteristic of Alzheimer’s disease and related dementias, but mechanisms of tau toxicity continue to be debated. Inherited mutations in tau cause early-onset frontotemporal lobar dementias (FTLD-tau) and are commonly used to model mechanisms of tau toxicity in tauopathies. Previous work in the isolated squid axoplasm model demonstrated that several pathogenic forms of tau inhibit axonal transport through a mechanism involving activation of protein phosphatase 1 (PP1). Here, we determined that P301L and R5L FTLD mutant tau proteins elicit a toxic effect on axonal transport as monomeric proteins. We also evaluated interactions between wild type and mutant tau with specific PP1 isoforms (α, β and γ), further examining their contribution to this toxic effect using primary rat hippocampal neurons from both sexes. Pulldown and bioluminescence resonance energy transfer experiments revealed selective interactions of wild type tau with PP1α and PP1γ isoforms, but not PP1β, whic...

Human behavior is biased by past experience. For example, when intercepting a moving target, the speed of previous targets will bias responses in future trials. Neural mechanisms underlying this so-called serial dependence are still under debate. Here, we tested the hypothesis that the previous trial leaves a neural trace in brain regions associated with encoding task-relevant information in visual and/or motor regions. We reasoned that injecting noise by means of transcranial magnetic stimulation (TMS) over premotor and visual areas would degrade such memory traces and hence reduce serial dependence. To test this hypothesis, we applied bursts of TMS pulses to right visual motion processing region hV5/MT+ and to left dorsal premotor cortex during inter-trial intervals of a coincident timing task performed by twenty healthy human participants (15 female). Without TMS, participants presented a bias towards the speed of the previous trial when intercepting moving targets. TMS over dorsal premotor cortex decre...

Frustrative nonreward is a construct in the Negative Valence Systems domain of the Research Domain Criteria (RDoC) from the US National Institute of Mental Health. An organism’s response to frustrating situations (e.g. inability to obtain an expected reward) has broad implications for a variety of neuropsychiatric conditions, including substance use disorders. The current project developed a first of its kind rat operant behavioral model of frustrative nonreward based loosely on the human Point Subtraction Aggression Paradigm. The current study shows that individual differences in frustrative nonreward for sucrose pellets are consistent across sessions at baseline and that the task is sensitive to reward size in male rats. More importantly, high frustrative nonreward behavior for sucrose predicts early “breaking” for intravenous fentanyl self-administration under a progressive ratio schedule. These results solidify frustration/frustrative nonreward as an important factor for substance use disorders in addi...

The transcription factor CREB is involved in a myriad of cellular functions in the central nervous system. For instance, the role of CREB via phosphorylation at the amino-acid residue Serine (Ser) 133 in expressing plasticity-related genes and activity-dependent neuronal plasticity processes has been extensively demonstrated. However, much less is known about the role of CREB phosphorylation at Ser 142 and 143. Here, we employed a viral vector containing a dominant negative form of CREB, with serine-to-alanine mutations at residue 142 and 143 to specifically block phosphorylation at both sites. We then transfected this vector into primary neurons in vitro or intra-cortically injected it into mice in vivo, to test if these phosphorylation events were important for activity-dependent plasticity. We demonstrated by immunohistochemistry of cortical neuronal cultures that the expression of Arc, a known plasticity-related gene, requires triple phosphorylation of CREB at Ser 133, 142, and 143. Moreover, we record...

The ability to adapt under significant adversity, defined as psychological resilience, is instrumental in preventing stress-related disorders. An important aspect of resilience is the capacity to endure affective distress when in pursuit of goals, also known as distress tolerance. Evidence that links intrinsic baseline interactions within large-scale functional networks with performance under distress remains missing. We hypothesized that the anterior cingulate cortex (ACC) may engage in distress tolerance due to its involvement in attention and emotion regulation. Accordingly, we tested whether behavioral performance under distress is associated with baseline resting-state ACC functional connectivity (FC). Distress tolerance was measured in 97 participants using the behavioral indicator of resiliency to distress (BIRD) task. Analyses contrasted participants who quit the task before its designated termination (n=51) with those who persisted throughout it (n=46). Seed-based FC analysis indicated greater con...

In oscillatory circuits, some actions of neuromodulators depend on the oscillation frequency. However, the mechanisms are poorly understood. We explored this problem by characterizing neuromodulation of the lateral pyloric (LP) neuron of the crab stomatogastric ganglion. Many peptide modulators, including proctolin, activate the same ionic current ( I MI) in stomatogastric neurons. Because I MI is fast and non-inactivating, its peak level does not depend on the temporal properties of neuronal activity. We found, however, that the amplitude and peak time of the proctolin-activated current in LP is frequency-dependent. Because frequency affects the rate of voltage change, we measured these currents with voltage ramps of different slopes and found that proctolin activated two kinetically distinct ionic currents: the known I MI, whose amplitude is independent of ramp slope or direction, and an inactivating current ( I MI-T), which was only activated by positive ramps and whose amplitude increased with increasi...

Adult-onset neurodegenerative diseases are often accompanied by evidence of a chronic inflammation that includes activation of microglial cells and altered levels of brain cytokines. Aspects of this response are likely secondary reactions to neurodegeneration, but for many illnesses the inflammation may itself be an early and even causative disease event. In such cases, the inflammation is referred to as "sterile" as it occurs in the absence of an actual bacterial or viral pathogen. A potent trigger of sterile inflammation in CNS microglia has been shown to be the presence of DNA in the cytoplasm (cytoDNA) induced either by direct DNA damage or by inhibited DNA repair. We have shown that cytoDNA comes from the cell nucleus as a result of insufficient DNA damage repair. Using wild type and Atm-/- mouse microglia, we extend these observations here by showing that its genomic origins are not random, but rather are heavily biased towards transcriptionally inactive, intergenic regions, in particular repetitive ...

Alpha activity (8–14 Hz) is the dominant rhythm in the awake brain, and thought to play an important role in setting the brain’s internal state. Previous work has associated states of decreased alpha power with enhanced neural excitability. However, evidence is mixed on whether and how such excitability enhancement modulates sensory signals of interest versus noise differently, and what, if any, the consequences are for subsequent perception. Here, human subjects (male and female) performed a visual detection task in which we manipulated their decision criteria in a block-wise manner. While our manipulation led to substantial criterion shifts, these shifts were not reflected in pre-stimulus alpha-band changes. Rather, lower pre-stimulus alpha power in occipital-parietal areas improved perceptual sensitivity and enhanced information content decodable from neural activity patterns. Additionally, oscillatory alpha phase immediately before stimulus presentation modulated accuracy. Together, our results suggest...

Visual representations can be generated via feedforward or feedback processes. The extent to which these processes result in overlapping representations remains unclear. Previous work has shown that imagined stimuli elicit similar representations as perceived stimuli throughout the visual cortex. However, while representations during imagery are indeed only caused by feedback processing, neural processing during perception is an interplay of both feedforward and feedback processing. This means that any representational overlap could be due to overlap in feedback processes. In the current study we aimed to investigate this issue by characterizing the overlap between feedforward- and feedback-initiated category-representations during imagery, conscious perception and unconscious processing using fMRI in humans of either sex. While all three conditions elicited stimulus representations in left lateral occipital cortex (LOC), significant similarities were only observed between imagery and conscious perception ...

Neurotransmitter spillover is a form of communication not readily predicted by anatomic structure. In the cerebellum, glutamate spillover from climbing fibers recruits molecular layer interneurons in the absence of conventional synaptic connections. Spillover-mediated signaling is typically limited by transporters that bind and reuptake glutamate. Here, we show that patterned expression of the excitatory amino acid transporter 4 (EAAT4) in Purkinje cells regulates glutamate spillover to molecular layer interneurons. Using male and female Aldolase C-Venus knock-in mice to visualize zebrin microzones, we find larger climbing fiber-evoked spillover EPSCs in regions with low levels of EAAT4 compared with regions with high EAAT4. This difference is not explained by presynaptic glutamate release properties or postsynaptic receptor density but rather by differences in the glutamate concentration reaching receptors on interneurons. Inhibiting glutamate transport normalizes the differences between microzones, sugge...