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J Neurosci [journal]
- Prenatal Deletion of the RNA-Binding Protein HuD Disrupts Postnatal Cortical Circuit Maturation and Behavior. [Journal Article]
- J Neurosci 2014 Mar 5; 34(10):3674-86.
The proper functions of cortical circuits are dependent upon both appropriate neuronal subtype specification and their maturation to receive appropriate signaling. These events establish a balanced circuit that is important for learning, memory, emotion, and complex motor behaviors. Recent research points to mRNA metabolism as a key regulator of this development and maturation process. Hu antigen D (HuD), an RNA-binding protein, has been implicated in the establishment of neuronal identity and neurite outgrowth in vitro. Therefore, we investigated the role of HuD loss of function on neuron specification and dendritogenesis in vivo using a mouse model. We found that loss of HuD early in development results in a defective early dendritic overgrowth phase and pervasive deficits in neuron specification in the lower neocortical layers and defects in dendritogenesis in the CA3 region of the hippocampus. Subsequent behavioral analysis revealed a deficit in performance of a hippocampus-dependent task: the Morris water maze. Further, HuD knock-out (KO) mice exhibited lower levels of anxiety than their wild-type counterparts and were overall less active. Last, we found that HuD KO mice are more susceptible to auditory-induced seizures, often resulting in death. Our findings suggest that HuD is necessary for the establishment of neocortical and hippocampal circuitry and is critical for their function.
- Age-Dependent, Non-Cell-Autonomous Deposition of Amyloid from Synthesis of β-Amyloid by Cells Other Than Excitatory Neurons. [Journal Article]
- J Neurosci 2014 Mar 5; 34(10):3668-73.
Rare, familial, early-onset autosomal dominant forms of familial Alzheimer's disease (FAD) are caused by mutations in genes encoding β-amyloid (Aβ) precursor protein (APP), presenilin-1 (PS1), and presenilin-2. Each of these genes is expressed ubiquitously throughout the CNS, but a widely held view is that excitatory neurons are the primary (or sole) source of the Aβ peptides that promote synaptic dysfunction and neurodegeneration. These efforts notwithstanding, APP and the enzymes required for Aβ production are synthesized by many additional cell types, and the degree to which those cells contribute to the production of Aβ that drives deposition in the CNS has not been tested. We generated transgenic mice in which expression of an ubiquitously expressed, FAD-linked mutant PSEN1 gene was selectively inactivated within postnatal forebrain excitatory neurons, with continued synthesis in all other cells in the CNS. When combined with an additional transgene encoding an FAD-linked APP "Swedish" variant that is synthesized broadly within the CNS, cerebral Aβ deposition during aging was found to be unaffected relative to mice with continued mutant PS1 synthesis in excitatory neurons. Thus, Aβ accumulation is non-cell autonomous, with the primary age-dependent contribution to cerebral Aβ deposition arising from mutant PS1-dependent cleavage of APP within cells other than excitatory neurons.
- Decreased Anxiety-Like Behavior and Gαq/11-Dependent Responses in the Amygdala of Mice Lacking TRPC4 Channels. [Journal Article]
- J Neurosci 2014 Mar 5; 34(10):3653-67.
Transient receptor potential (TRP) channels are abundant in the brain where they regulate transmission of sensory signals. The expression patterns of different TRPC subunits (TRPC1, 4, and 5) are consistent with their potential role in fear-related behaviors. Accordingly, we found recently that mutant mice lacking a specific TRP channel subunit, TRPC5, exhibited decreased innate fear responses. Both TRPC5 and another member of the same subfamily, TRPC4, form heteromeric complexes with the TRPC1 subunit (TRPC1/5 and TRPC1/4, respectively). As TRP channels with specific subunit compositions may have different functional properties, we hypothesized that fear-related behaviors could be differentially controlled by TRPCs with distinct subunit arrangements. In this study, we focused on the analysis of mutant mice lacking the TRPC4 subunit, which, as we confirmed in experiments on control mice, is expressed in brain areas implicated in the control of fear and anxiety. In behavioral experiments, we found that constitutive ablation of TRPC4 was associated with diminished anxiety levels (innate fear). Furthermore, knockdown of TRPC4 protein in the lateral amygdala via lentiviral-mediated gene delivery of RNAi mimicked the behavioral phenotype of constitutive TRPC4-null (TRPC4(-/-)) mouse. Recordings in brain slices demonstrated that these behavioral modifications could stem from the lack of TRPC4 potentiation in neurons in the lateral nucleus of the amygdala through two Gαq/11 protein-coupled signaling pathways, activated via Group I metabotropic glutamate receptors and cholecystokinin 2 receptors, respectively. Thus, TRPC4 and the structurally and functionally related subunit, TRPC5, may both contribute to the mechanisms underlying regulation of innate fear responses.
- Transcranial Direct Current Stimulation over Right Dorsolateral Prefrontal Cortex Enhances Error Awareness in Older Age. [Journal Article]
- J Neurosci 2014 Mar 5; 34(10):3646-52.
The ability to detect errors during cognitive performance is compromised in older age and in a range of clinical populations. This study was designed to assess the effects of transcranial direct current stimulation (tDCS) on error awareness in healthy older human adults. tDCS was applied over DLPFC while subjects performed a computerized test of error awareness. The influence of current polarity (anodal vs cathodal) and electrode location (left vs right hemisphere) was tested in a series of separate single-blind, Sham-controlled crossover trials, each including 24 healthy older adults (age 65-86 years). Anodal tDCS over right DLPFC was associated with a significant increase in the proportion of performance errors that were consciously detected, and this result was recapitulated in a separate replication experiment. No such improvements were observed when the homologous contralateral area was stimulated. The present study provides novel evidence for a causal role of right DLPFC regions in subserving error awareness and marks an important step toward developing tDCS as a tool for remediating the performance-monitoring deficits that afflict a broad range of populations.
- Noise in neural populations accounts for errors in working memory. [Journal Article]
- J Neurosci 2014 Mar 5; 34(10):3632-45.
Errors in short-term memory increase with the quantity of information stored, limiting the complexity of cognition and behavior. In visual memory, attempts to account for errors in terms of allocation of a limited pool of working memory resources have met with some success, but the biological basis for this cognitive architecture is unclear. An alternative perspective attributes recall errors to noise in tuned populations of neurons that encode stimulus features in spiking activity. I show that errors associated with decreasing signal strength in probabilistically spiking neurons reproduce the pattern of failures in human recall under increasing memory load. In particular, deviations from the normal distribution that are characteristic of working memory errors and have been attributed previously to guesses or variability in precision are shown to arise as a natural consequence of decoding populations of tuned neurons. Observers possess fine control over memory representations and prioritize accurate storage of behaviorally relevant information, at a cost to lower priority stimuli. I show that changing the input drive to neurons encoding a prioritized stimulus biases population activity in a manner that reproduces this empirical tradeoff in memory precision. In a task in which predictive cues indicate stimuli most probable for test, human observers use the cues in an optimal manner to maximize performance, within the constraints imposed by neural noise.
- Compensatory changes accompanying chronic forced use of the nondominant hand by unilateral amputees. [Journal Article]
- J Neurosci 2014 Mar 5; 34(10):3622-31.
Amputation of the dominant hand forces patients to use the nondominant hand exclusively, including for tasks (e.g., writing and drawing) that were formerly the sole domain of the dominant hand. The behavioral and neurological effects of this chronic forced use of the nondominant hand remain largely unknown. Yet, these effects may shed light on the potential to compensate for degradation or loss of dominant hand function, as well as the mechanisms that support motor learning under conditions of very long-term training. We used a novel precision drawing task and fMRI to investigate 8 adult human amputees with chronic (mean 33 years) unilateral dominant (right) hand absence, and right-handed matched controls (8 for fMRI, 19 for behavior). Amputees' precision drawing performances with their left hands reached levels of smoothness (associated with left hemisphere control), acceleration time (associated with right hemisphere control), and speed equivalent to controls' right hands, whereas accuracy maintained a level comparable with controls' left hands. This compensation is supported by an experience-dependent shift from heavy reliance on the dorsodorsal parietofrontal pathway (feedback control) to the ventrodorsal pathway and prefrontal regions involved in the cognitive control of goal-directed actions. Relative to controls, amputees also showed increased activity within the former cortical sensorimotor hand territory in the left (ipsilateral) hemisphere. These data demonstrate that, with chronic and exclusive forced use, the speed and quality of nondominant hand precision endpoint control in drawing can achieve levels nearly comparable with the dominant hand.
- Acute suppressive and long-term phase modulation actions of orexin on the Mammalian circadian clock. [Journal Article]
- J Neurosci 2014 Mar 5; 34(10):3607-21.
Circadian and homeostatic neural circuits organize the temporal architecture of physiology and behavior, but knowledge of their interactions is imperfect. For example, neurons containing the neuropeptide orexin homeostatically control arousal and appetitive states, while neurons in the suprachiasmatic nuclei (SCN) function as the brain's master circadian clock. The SCN regulates orexin neurons so that they are much more active during the circadian night than the circadian day, but it is unclear whether the orexin neurons reciprocally regulate the SCN clock. Here we show both orexinergic innervation and expression of genes encoding orexin receptors (OX1 and OX2) in the mouse SCN, with OX1 being upregulated at dusk. Remarkably, we find through in vitro physiological recordings that orexin predominantly suppresses mouse SCN Period1 (Per1)-EGFP-expressing clock cells. The mechanisms underpinning these suppressions vary across the circadian cycle, from presynaptic modulation of inhibitory GABAergic signaling during the day to directly activating leak K(+) currents at night. Orexin also augments the SCN clock-resetting effects of neuropeptide Y (NPY), another neurochemical correlate of arousal, and potentiates NPY's inhibition of SCN Per1-EGFP cells. These results build on emerging literature that challenge the widely held view that orexin signaling is exclusively excitatory and suggest new mechanisms for avoiding conflicts between circadian clock signals and homeostatic cues in the brain.
- A polyaxonal amacrine cell population in the primate retina. [Journal Article]
- J Neurosci 2014 Mar 5; 34(10):3597-606.
Amacrine cells are the most diverse and least understood cell class in the retina. Polyaxonal amacrine cells (PACs) are a unique subset identified by multiple long axonal processes. To explore their functional properties, populations of PACs were identified by their distinctive radially propagating spikes in large-scale high-density multielectrode recordings of isolated macaque retina. One group of PACs exhibited stereotyped functional properties and receptive field mosaic organization similar to that of parasol ganglion cells. These PACs had receptive fields coincident with their dendritic fields, but much larger axonal fields, and slow radial spike propagation. They also exhibited ON-OFF light responses, transient response kinetics, sparse and coordinated firing during image transitions, receptive fields with antagonistic surrounds and fine spatial structure, nonlinear spatial summation, and strong homotypic neighbor electrical coupling. These findings reveal the functional organization and collective visual signaling by a distinctive, high-density amacrine cell population.
- Attention Improves Transfer of Motion Information between V1 and MT. [Journal Article]
- J Neurosci 2014 Mar 5; 34(10):3586-96.
Selective attention modulates activity within individual visual areas; however, the role of attention in mediating the transfer of information between areas is not well understood. Here, we used fMRI to assess attention-related changes in coupled BOLD activation in two key areas of human visual cortex that are involved in motion processing: V1 and MT. To examine attention-related changes in cross-area coupling, multivoxel patterns in each visual area were decomposed to estimate the trial-by-trial response amplitude in a set of direction-selective "channels." In both V1 and MT, BOLD responses increase in direction-selective channels tuned to the attended direction of motion and decrease in channels tuned away from the attended direction. Furthermore, the modulation of cross-area correlations between similarly tuned populations is inversely related to the modulation of their mean responses, an observation that can be explained via a feedforward motion computation in MT and a modulation of local noise correlations in V1. More importantly, these modulations accompany an increase in the cross-area mutual information between direction-selective response patterns in V1 and MT, suggesting that attention improves the transfer of sensory information between cortical areas that cooperate to support perception. Finally, our model suggests that divisive normalization of neural activity in V1 before its integration by MT is critical to cross-area information coupling, both in terms of cross-area correlation as well as cross-area mutual information.
- Decision-related activity in sensory neurons may depend on the columnar architecture of cerebral cortex. [Journal Article]
- J Neurosci 2014 Mar 5; 34(10):3579-85.
Many studies have reported correlations between the activity of sensory neurons and animals' judgments in discrimination tasks. Here, we suggest that such neuron-behavior correlations may require a cortical map for the task relevant features. This would explain why studies using discrimination tasks based on disparity in area V1 have not found these correlations: V1 contains no map for disparity. This scheme predicts that activity of V1 neurons correlates with decisions in an orientation-discrimination task. To test this prediction, we trained two macaque monkeys in a coarse orientation discrimination task using band-pass-filtered dynamic noise. The two orientations were always 90° apart and task difficulty was controlled by varying the orientation bandwidth of the filter. While the trained animals performed this task, we recorded from orientation-selective V1 neurons (n = 82, n = 31 for Monkey 1, n = 51 for Monkey 2). For both monkeys, we observed significant correlation (quantified as "choice probabilities") of the V1 activity with the monkeys' perceptual judgments (mean choice probability 0.54, p = 10(-5)). In one of these animals, we had previously measured choice probabilities in a disparity discrimination task in V1, which had been at chance (0.49, not significantly different from 0.5). The choice probabilities in this monkey for the orientation discrimination task were significantly larger than those for the disparity discrimination task (p = 0.032). These results are predicted by our suggestion that choice probabilities are only observed for cortical sensory neurons that are organized in maps for the task-relevant feature.