The Journal of neuroscience : the official journal of the Society for Neuroscience
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The posterior parietal cortex (PPC) has traditionally been considered important for awareness, spatial perception, and attention. However, recent findings provide evidence that the PPC also encodes information important for making decisions. These findings have initiated a running argument of whether the PPC is critically involved in decision making. To examine this issue, we reversibly inactivated the parietal reach region (PRR), the area of the PPC that is specialized for reaching movements, while two monkeys performed a memory-guided reaching or saccade task. The task included choices between two equally rewarded targets presented simultaneously in opposite visual fields. Free-choice trials were interleaved with instructed trials, in which a single cue presented in the peripheral visual field defined the reach and saccade target unequivocally. We found that PRR inactivation led to a strong reduction of contralesional choices, but only for reaches. On the other hand, saccade choices were not affected by PRR inactivation. Importantly, reaching and saccade movements to single instructed targets remained largely intact. These results cannot be explained as an effector-nonspecific deficit in spatial attention or awareness, since the temporary "lesion" had an impact only on reach choices. Hence, the PPR is a part of a network for reach decisions and not just reach planning. ⋯ There has been an ongoing debate on whether the posterior parietal cortex (PPC) represents only spatial awareness, perception, and attention or whether it is also involved in decision making for actions. In this study we explore whether the parietal reach region (PRR), the region of the PPC that is specialized for reaches, is involved in the decision process. We inactivated the PRR while two monkeys performed reach and saccade choices between two targets presented simultaneously in both hemifields. We found that inactivation affected only the reach choices, while leaving saccade choices intact. These results cannot be explained as a deficit in attention, since the temporary lesion affected only the reach choices. Thus, PRR is a part of a network for making reach decisions.
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Following the discovery of the antidepressant properties of ketamine, there has been a recent resurgence in the interest in this NMDA receptor antagonist. Although detailed animal models of the molecular mechanisms underlying ketamine's effects have emerged, there are few MEG/EEG studies examining the acute subanesthetic effects of ketamine infusion in man. We recorded 275 channel MEG in two experiments (n = 25 human males) examining the effects of subanesthetic ketamine infusion. MEG power spectra revealed a rich set of significant oscillatory changes compared with placebo sessions, including decreases in occipital, parietal, and anterior cingulate alpha power, increases in medial frontal theta power, and increases in parietal and cingulate cortex high gamma power. Each of these spectral effects demonstrated their own set of temporal dynamics. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants' self-reports of blissful state. Based on these results, we suggest that the antidepressant effects of ketamine may depend on its ability to change the balance of frontoparietal connectivity patterns. ⋯ In this paper, we found that subanesthetic doses of ketamine, similar to those used in antidepressant studies, increase anterior theta and gamma power but decrease posterior theta, delta, and alpha power, as revealed by magnetoencephalographic recordings. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants' self-reports of blissful state. The alterations in frontoparietal connectivity patterns we observe here may be important in generating the antidepressant response to ketamine.
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Alzheimer's disease (AD) is a frequent and irreversible age-related neurodegeneration without efficient treatment. Experimental AD in mice responds positively to decreased insulin-like growth factor I (IGF-I) signaling, a pathway also implicated in aging. Here we aimed to protect the aging brain from devastating amyloid pathology by making specifically adult neurons resistant to IGF signaling. To achieve that, we knocked out neuronal IGF-1R during adulthood in APP/PS1 mice. We found that mutants exhibited improved spatial memory and reduced anxiety. Mutant brains displayed fewer amyloid plaques, less amyloid-β (Aβ), and diminished neuroinflammation. Surprisingly, adult neurons undergoing IGF-1R knock-out reduced their apical soma and developed leaner dendrites, indicative of remarkable structural plasticity entailing condensed forebrain neuroarchitecture. Neurons lacking IGF-1R in AD showed less accumulation of Aβ-containing autophagic vacuoles. At the same time, plasma Aβ levels were increased. Our data indicate that neuronal IGF-1R ablation, via preserved autophagic compartment and enhanced systemic elimination, offers lifelong protection from AD pathology by clearing toxic Aβ. Neuronal IGF-1R, and possibly other cell size-controlling pathways are promising targets for AD treatment. ⋯ We found compelling evidence in vivo that Alzheimer's disease (AD) progression is significantly delayed when insulin-like growth factor (IGF) signaling is blocked in adult neurons. To show that, we built a novel mouse model, combining inducible neuron-specific IGF-1R knock-out with AD transgenics. Analysis of the experimental AD phenotype revealed less abundant amyloid-β (Aβ) peptides, fewer plaques, and diminished neuroinflammation in mutants with inactivated IGF signaling, together with clearly preserved behavioral and memory performances. We present for the first time evidence that IGF signaling has profound effects on neuronal proteostasis and maintenance of cell morphology in vivo. Our results indicate in a model highly pertinent to translational research that neuronal IGF resistance may represent a pathophysiologically relevant mechanism of the brain for preventing Aβ accumulation.
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The therapeutic potential of histone deacetylase inhibitor (HDACi) treatment has attracted considerable attention in the emerging area of cognitive neuroepigenetics. The possibility that ongoing cognitive experience importantly regulates the cell biological effects of HDACi administration, however, has not been systematically examined. In an initial experiment addressing this issue, we tested whether water maze training influences the gene expression response to acute systemic HDACi administration in the young adult rat hippocampus. Training powerfully modulated the response to HDACi treatment, increasing the total number of genes regulated to nearly 3000, including many not typically linked to neural plasticity, compared with <300 following HDACi administration alone. Although water maze training itself also regulated nearly 1800 genes, the specific mRNAs, gene networks, and biological pathways involved were largely distinct when the same experience was provided together with HDACi administration. Next, we tested whether the synaptic protein response to HDACi treatment is similarly dependent on recent cognitive experience, and whether this plasticity is altered in aged rats with memory impairment. Whereas synaptic protein labeling in the young hippocampus was selectively increased when HDACi administration was provided in conjunction with water maze training, combined treatment had no effect on synaptic proteins in the aged hippocampus. Our findings indicate that ongoing experience potently regulates the molecular consequences of HDACi treatment and that the interaction of recent cognitive experience with histone acetylation dynamics is disrupted in the aged hippocampus. ⋯ The possibility that interventions targeting epigenetic regulation could be effective in treating a range of neurodegenerative disorders has attracted considerable interest. Here we demonstrate in the rat hippocampus that ongoing experience powerfully modifies the molecular response to one such intervention, histone deacetylase inhibitor (HDACi) administration. A single learning episode dramatically shifts the gene expression profile induced by acute HDACi treatment, yielding a qualitatively distinct hippocampal transcriptome compared with the influence of behavioral training alone. The downstream synaptic protein response to HDACi administration is similarly experience-dependent, and we report that this plasticity is disrupted in the aged hippocampus. The findings highlight that accommodating the modulatory influence of ongoing experience represents a challenge for therapeutic development in the area of cognitive neuroepigenetics.
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Adaptive behavior relies on combining bottom-up sensory inputs with top-down control signals to guide responses in line with current goals and task demands. Over the past decade, accumulating evidence has suggested that the dorsal and ventral frontoparietal attentional systems are recruited interactively in this process. This fMRI study used concurrent transcranial magnetic stimulation (TMS) as a causal perturbation approach to investigate the interactions between dorsal and ventral attentional systems and sensory processing areas. In a sustained spatial attention paradigm, human participants detected weak visual targets that were presented in the lower-left visual field on 50% of the trials. Further, we manipulated the presence/absence of task-irrelevant auditory signals. Critically, on each trial we applied 10 Hz bursts of four TMS (or Sham) pulses to the intraparietal sulcus (IPS). IPS-TMS relative to Sham-TMS increased activation in the parietal cortex regardless of sensory stimulation, confirming the neural effectiveness of TMS stimulation. Visual targets increased activations in the anterior insula, a component of the ventral attentional system responsible for salience detection. Conversely, they decreased activations in the ventral visual areas. Importantly, IPS-TMS abolished target-evoked activation increases in the right temporoparietal junction (TPJ) of the ventral attentional system, whereas it eliminated target-evoked activation decreases in the right fusiform. Our results demonstrate that IPS-TMS exerts profound directional causal influences not only on visual areas but also on the TPJ as a critical component of the ventral attentional system. They reveal a complex interplay between dorsal and ventral attentional systems during target detection under sustained spatial attention. ⋯ Adaptive behavior relies on combining bottom-up sensory inputs with top-down attentional control. Although the dorsal and ventral frontoparietal systems are key players in attentional control, their distinct contributions remain unclear. In this TMS-fMRI study, participants attended to the left visual field to detect weak visual targets presented on half of the trials. We applied brief TMS bursts (or Sham-TMS) to the dorsal intraparietal sulcus (IPS) 100 ms after visual stimulus onset. IPS-TMS abolished the visual induced response suppression in the ventral occipitotemporal cortex and the response enhancement to visual targets in the temporoparietal junction. Our results demonstrate that IPS causally influences neural activity in the ventral attentional system 100 ms poststimulus. They have important implications for our understanding of the neural mechanisms underlying attentional control.