Mapping neural dynamics underlying saccade preparation and execution and their relation to reaction time and direction errors.

Our ability to control and inhibit automatic behaviors is crucial for negotiating complex environments, all of which require rapid communication between sensory, motor, and cognitive networks. Here, we measured neuromagnetic brain activity to investigate the neural timing of cortical areas needed for inhibitory control, while 14 healthy young adults performed an interleaved prosaccade (look at a peripheral visual stimulus) and antisaccade (look away from stimulus) task. Analysis of how neural activity relates to saccade reaction time (SRT) and occurrence of direction errors (look at stimulus on antisaccade trials) provides insight into inhibitory control. Neuromagnetic source activity was used to extract stimulus-aligned and saccade-aligned activity to examine temporal differences between prosaccade and antisaccade trials in brain regions associated with saccade control. For stimulus-aligned antisaccade trials, a longer SRT was associated with delayed onset of neural activity within the ipsilateral parietal eye field (PEF) and bilateral frontal eye field (FEF). Saccade-aligned activity demonstrated peak activation 10ms before saccade-onset within the contralateral PEF for prosaccade trials and within the bilateral FEF for antisaccade trials. In addition, failure to inhibit prosaccades on anti-saccade trials was associated with increased activity prior to saccade onset within the FEF contralateral to the peripheral stimulus. This work on dynamic activity adds to our knowledge that direction errors were due, at least in part, to a failure to inhibit automatic prosaccades. These findings provide novel evidence in humans regarding the temporal dynamics within oculomotor areas needed for saccade programming and the role frontal brain regions have on top-down inhibitory control.

Insulin Resistance as a Shared Pathogenic Mechanism Between Depression and Type 2 Diabetes.

Neuropsychiatric disorders and type 2 diabetes (T2D) are major public health concerns proposed to be intimately connected. T2D is associated with increased risk of dementia, neuropsychiatric and mood disorders. Evidences of the involvement of insulin signaling on brain mechanisms related to depression indicate that insulin resistance, a hallmark of type 2 diabetes, could develop in the brains of depressive patients. In this article, we briefly review possible molecular mechanisms associating defective brain insulin signaling with reward system, neurogenesis, synaptic plasticity and hypothalamic-pituitary-adrenal (HPA) stress axis in depression. We further discuss the involvement of tumor necrosis factor α (TNFα) promoting defective insulin signaling and depressive-like behavior in rodent models. Finally, due to the high resistant rate of anti-depressants, novel insights into the link between insulin resistance and depression may advance the development of alternative treatments for this disease.

Alzheimer-associated Aß oligomers impact the central nervous system to induce peripheral metabolic deregulation.

Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated Aß oligomers (AßOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AßOs failed to induce glucose intolerance, suggesting AßOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AßOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation (eIF2α-P). AßOs further induced eIF2α-P and activated pro-inflammatory IKKß/NF-κB signaling in the hypothalamus of mice and macaques. AßOs failed to trigger peripheral glucose intolerance in tumor necrosis factor-α (TNF-α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AßOs act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that AßOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD.

TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's ß-amyloid oligomers in mice and monkeys.

Alzheimer's disease (AD) and type 2 diabetes appear to share similar pathogenic mechanisms. dsRNA-dependent protein kinase (PKR) underlies peripheral insulin resistance in metabolic disorders. PKR phosphorylates eukaryotic translation initiation factor 2α (eIF2α-P), and AD brains exhibit elevated phospho-PKR and eIF2α-P levels. Whether and how PKR and eIF2α-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that ß-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor α (TNF-α)-dependent manner, resulting in eIF2α-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2α-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2α-P and cognitive impairment in PKR(-/-) and TNFR1(-/-) mice. Bolstering insulin signaling rescued phospho-PKR and eIF2α-P. Results reveal pathogenic mechanisms shared by AD and diabetes and establish that proinflammatory signaling mediates oligomer-induced IRS-1 inhibition and PKR-dependent synapse and memory loss.

Threshold mechanism for saccade initiation in frontal eye field and superior colliculus.

In an influential model of frontal eye field (FEF) and superior colliculus (SC) activity, saccade initiation occurs when the discharge rate of either single neurons or a population of neurons encoding a saccade motor plan reaches a threshold level of activity. Conflicting evidence exists for whether this threshold is fixed or can change under different conditions. We tested the fixed-threshold hypothesis at the single-neuron and population levels to help resolve the inconsistency between previous studies. Two rhesus monkeys performed a randomly interleaved pro- and antisaccade task in which they had to look either toward (pro) or 180° away (anti) from a peripheral visual stimulus. We isolated visuomotor (VM) and motor (M) neurons in the FEF and SC and tested three specific predictions of a fixed-threshold hypothesis. We found little support for fixed thresholds. First, correlations were never totally absent between presaccadic discharge rate and saccadic reaction time when examining a larger (plausible) temporal period. Second, presaccadic discharge rates varied markedly between saccade tasks. Third, visual responses exceeded presaccadic motor discharges for FEF and SC VM neurons. We calculated that only a remarkably strong bias for M neurons in downstream projections could render the fixed-threshold hypothesis plausible at the population level. Also, comparisons of gap vs. overlap conditions indicate that increased inhibitory tone may be associated with stability of thresholds. We propose that fixed thresholds are the exception rather than the rule in FEF and SC, and that stabilization of an otherwise variable threshold depends on task-related, inhibitory modulation.

An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aß oligomers.

Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-ß peptide (Aß) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aß oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.

Neural correlates of conflict resolution between automatic and volitional actions by basal ganglia.

A dominant basal ganglia (BG) model consists of two functionally opposite pathways: one facilitates motor output and the other suppresses it. Although this idea was originally proposed to account for motor deficits, it has been extended recently also to explain cognitive deficits. Here, we employed the antisaccade paradigm (look away from a stimulus) to address the role of the caudate nucleus, the main BG input stage where the two pathways diverge, in conflict resolution. Using single neuron recordings in awake monkeys, we identified the following three groups of neurons. The first group of neurons showed activity consistent with sensory-driven (automatic) saccades toward a contralateral visual stimulus. The second group of neurons showed activity consistent with internally driven (volitional) saccades toward the contralateral side regardless of stimulus locations. The third group of neurons showed similar firing characteristics with the second group of neurons, except that their preferred saccade direction was ipsilateral. The activity of the three groups of neurons was correlated with behavioral outcome. Based on these findings, we suggest the following hypothesis: the first and second groups of neurons encoding automatic and volitional saccades, respectively, might give rise to the facilitation (direct) pathway and promote saccades toward the opposite directions, which creates a response conflict. This conflict could be resolved by the third group of caudate neurons, which might give rise to the suppression (indirect) pathway and attenuate inappropriate saccade commands toward the stimulus.