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- Neurocognitive Problems in Children and Adolescents With Depression Using the CHC Theory and the WJ-III. [JOURNAL ARTICLE]
- Appl Neuropsychol Child 2014 Nov 20.:1-9.
Depression has been commonly associated with both subjective complaints and objectively measured problems in cognition. Most commonly discussed in relation to the adult population, growing evidence has supported the idea that children and adolescents experience cognitive problems in relation to depression. The purpose of this study was to further examine the negative influence of depression on the cognitive functioning of children and adolescents. Additionally, the present study evaluated the sensitivity of the Woodcock-Johnson III Test of Cognitive Abilities (WJ-III-COG) and, in turn, the Cattell-Horn-Carroll (CHC) theory in measuring cognitive problems related to depression in children and adolescents. Participants included 420 children and adolescents aged 8 to 18 years old (M = 13.09, SD = 2.95) with a clinical diagnosis of depression. Comparisons were made against the normative mean. All participants completed 11 subtests of the WJ-III-COG including Visual-Auditory Learning, Spatial Relations, Sound Blending, Concept Formations, Visual Matching, Numbers Reversed, Auditory-Working Memory, Picture Recognition, Analysis Synthesis, Decision Speed, and Memory for Words. Children and adolescents with depression demonstrated significantly lower performance on subtests related to learning and memory (long-term retrieval), attentional capacity, working memory, reasoning, and processing speed. No problems were noted on subtests related to visual-spatial thinking and auditory processing. Findings suggested sensitivity of the WJ-III-COG and CHC theory in identifying cognitive problems associated with depression in children and adolescents.
- Long-lasting suppression of acoustic startle response following mild traumatic brain injury. [JOURNAL ARTICLE]
- J Neurotrauma 2014 Nov 20.
Acoustic startle response (ASR) is a defensive reflex that is largely ignored unless greatly exaggerated. ASR is suppressed following moderate and severe TBI, but the effect of mild TBI (mTBI) on ASR has not been investigated. Because the neural circuitry for ASR resides in the pons in all mammals, ASR may be a good measure of brainstem function following mTBI. The present study assessed ASR in Sprague Dawley rats following mTBI using lateral fluid percussion and compared these effects to those on spatial working memory. mTBI caused a profound and long-lasting suppression of ASR. Both probability of emitting a startle and startle amplitude were diminished. ASR suppression was observed as soon as 1 day after injury and remained suppressed for the duration of the study (21 days after injury). No indication of recovery was observed. mTBI also impaired spatial working memory. In contrast to the suppression of ASR, working memory impairment was transient; memory was impaired 1 and 7 days following injury, but recovered by 21 days. The long-lasting suppression of ASR suggests long-term dysfunction of brainstem neural circuits at a time when forebrain neural circuits responsible for spatial working memory have recovered. These results have important implications for return to activity decisions because recovery of cognitive impairments plays an important role in these decisions.
- Long-Term Memory Stabilized by Noise-Induced Rehearsal. [JOURNAL ARTICLE]
- J Neurosci 2014 Nov 19; 34(47):15804-15815.
Cortical networks can maintain memories for decades despite the short lifetime of synaptic strengths. Can a neural network store long-lasting memories in unstable synapses? Here, we study the effects of ongoing spike-timing-dependent plasticity (STDP) on the stability of memory patterns stored in synapses of an attractor neural network. We show that certain classes of STDP rules can stabilize all stored memory patterns despite a short lifetime of synapses. In our model, unstructured neural noise, after passing through the recurrent network connections, carries the imprint of all memory patterns in temporal correlations. STDP, combined with these correlations, leads to reinforcement of all stored patterns, even those that are never explicitly visited. Our findings may provide the functional reason for irregular spiking displayed by cortical neurons and justify models of system memory consolidation. Therefore, we propose that irregular neural activity is the feature that helps cortical networks maintain stable connections.
- The Inherent Premise of Immunotherapy for Cancer Dormancy. [REVIEW]
- Cancer Res 2014 Nov 19.
Clinical cancer dormancy is evident from the detection of circulating tumor cells in the blood and tissue-residing disseminated tumor cells in the bone marrow of cancer survivors who have been clinically disease free. Emerging evidence from clinical and preclinical studies suggests that tumor dormancy is a critical step in the development of both primary cancer and advanced-stage disease. In this review, it is shown that (i) naturally occurring tumor dormancy precedes occurrence of primary cancer, and (ii) conventional cancer therapies result in treatment-induced tumor dormancy, which in turn could lead to distant recurrence of cancer or permanent tumor dormancy, depending on immunogenic status of dormancy. Given that cellular dormancy is an evolutionary conserved survival mechanism in biologic systems, any stress or cytotoxic therapy could trigger cellular dormancy. Therefore, a successful cancer therapy is likely to be achieved by establishing permanent tumor dormancy and preventing distant recurrence of cancer or by eliminating dormant tumor cells. This could be accomplished by cancer immunotherapy because of the establishment of long-term memory responses. Cancer Res; 74(23); 1-5. ©2014 AACR.
- Epigenetics of Depression. [JOURNAL ARTICLE]
- Prog Mol Biol Transl Sci 2014.:103-137.
Major depressive disorder (MDD) is a leading cause of disability worldwide and is associated with poor psychological, medical, and socioeconomic outcomes. Although much has been learned about the etiology and treatment options of MDD over the past decade, there remain unanswered questions that pose challenges to improving acute and chronic outcomes for those with MDD. MDD is a clinically heterogeneous disorder. Genetic studies to date have indicated a number of genes, including transporters, neurotransmitters, neurotrophins, and their associated signaling networks that may predispose individuals to MDD and may also predict treatment outcomes. However, twin studies indicate that genes account for only a small degree of the variation in MDD. Thus, other mechanisms, through epigenetic marks, may act to form a molecular memory of previous gene-to-environment interactions and to establish vulnerabilities (or, conversely, resistance) to MDD. Current evidence supports a role for pre-, peri-, and early postnatal adversities and stressful life events into adulthood affecting epigenetic patterns, providing a mechanistic foundation to develop epigenetic marks as biomarkers for MDD. This review presents the evidence supporting a role for epigenetic effects in MDD and in treatment response. We also discuss the controversy behind modulating epigenetic mechanisms in long-term antidepressant pharmacotherapy.
- The Epigenetic Basis of Memory Formation and Storage. [JOURNAL ARTICLE]
- Prog Mol Biol Transl Sci 2014.:1-27.
The formation of long-term memory requires a series of cellular and molecular changes that involve transcriptional regulation of gene expression. While these changes in gene transcription were initially thought to be largely regulated by the activation of transcription factors by intracellular signaling molecules, epigenetic mechanisms have emerged as an important regulator of transcriptional processes across multiple brain regions to form a memory circuit for a learned event or experience. Due to their self-perpetuating nature and ability to bidirectionally control gene expression, these epigenetic mechanisms have the potential to not only regulate initial memory formation but also modify and update memory over time. This chapter focuses on the established, but poorly understood, role for epigenetic mechanisms such as posttranslational modifications of histone proteins and DNA methylation at the different stages of memory storage. Additionally, this chapter emphasizes how these mechanisms interact to control the ideal epigenetic environment for memory formation and modification in neurons. The reader will gain insights into the limitations in our current understanding of epigenetic regulation of memory storage, especially in terms of their cell-type specificity and the lack of understanding in the interactions of various epigenetic modifiers to one another to impact gene expression changes during memory formation.
- A rodent model of mild traumatic brain blast injury. [JOURNAL ARTICLE]
- J Neurosci Res 2014 Nov 19.
One of the criteria defining mild traumatic brain injury (mTBI) in humans is a loss of consciousness lasting for less than 30 min. mTBI can result in long-term impairment of cognition and behavior. In rats, the length of time it takes a rat to right itself after injury is considered to be an analog for human return to consciousness. This study characterized a rat mild brain blast injury (mBBI) model defined by a righting response reflex time (RRRT) of more than 4 min but less than 10 min. Assessments of motor coordination relying on beam-balance and foot-fault assays and reference memory showed significant impairment in animals exposed to mBBI. This study's hypothesis is that there are inflammatory outcomes to mTBI over time that cause its deleterious effects. For example, mBBI significantly increased brain levels of interleukin (IL)-1β and tumor necrosis factor-α (TNFα) protein. There were significant inflammatory responses in the cortex, hippocampus, thalamus, and amygdala 6 hr after mBBI, as evidenced by increased levels of the inflammatory markers associated with activation of microglia and macrophages, ionized calcium binding adaptor 1 (IBA1), impairment of the blood-brain barrier, and significant neuronal losses. There were significant increases in phosphorylated Tau (p-Tau) levels, a putative precursor to the development of neuroencephalopathy, as early as 6 hr after mBBI in the cortex and the hippocampus but not in the thalamus or the amygdala. There was an apparent correlation between RRRTs and p-Tau protein levels but not IBA1. These results suggest potential therapies for mild blast injuries via blockade of the IL-1β and TNFα receptors. © 2014 Wiley Periodicals, Inc.
- Neural ECM proteases in learning and synaptic plasticity. [JOURNAL ARTICLE]
- Prog Brain Res 2014.:135-157.
Recent studies implicate extracellular proteases in synaptic plasticity, learning, and memory. The data are especially strong for such serine proteases as thrombin, tissue plasminogen activator, neurotrypsin, and neuropsin as well as matrix metalloproteinases, MMP-9 in particular. The role of those enzymes in the aforementioned phenomena is supported by the experimental results on the expression patterns (at the gene expression and protein and enzymatic activity levels) and functional studies, including knockout mice, specific inhibitors, etc. Counterintuitively, the studies have shown that the extracellular proteolysis is not responsible mainly for an overall degradation of the extracellular matrix (ECM) and loosening perisynaptic structures, but rather allows for releasing signaling molecules from the ECM, transsynaptic proteins, and latent form of growth factors. Notably, there are also indications implying those enzymes in the major neuropsychiatric disorders, probably by contributing to synaptic aberrations underlying such diseases as schizophrenia, bipolar, autism spectrum disorders, and drug addiction.
- Neuroligin-associated microRNA-932 targets actin and regulates memory in the honeybee. [JOURNAL ARTICLE]
- Nat Commun 2014.:5529.
Increasing evidence suggests small non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) control levels of mRNA expression during experience-related remodelling of the brain. Here we use an associative olfactory learning paradigm in the honeybee Apis mellifera to examine gene expression changes in the brain during memory formation. Brain transcriptome analysis reveals a general downregulation of protein-coding genes, including asparagine synthetase and actin, and upregulation of ncRNAs. miRNA-mRNA network predictions together with PCR validation suggest miRNAs including miR-210 and miR-932 target the downregulated protein-coding genes. Feeding cholesterol-conjugated antisense RNA to bees results in the inhibition of miR-210 and of miR-932. Loss of miR-932 impairs long-term memory formation, but not memory acquisition. Functional analyses show that miR-932 interacts with Act5C, providing evidence for direct regulation of actin expression by an miRNA. An activity-dependent increase in miR-932 expression may therefore control actin-related plasticity mechanisms and affect memory formation in the brain.
- Synaptic plasticity and cognitive function are disrupted in the absence of Lrp4. [JOURNAL ARTICLE]
- Elife 2014 Nov 19.
Lrp4, the muscle receptor for neuronal Agrin, is expressed in the hippocampus and areas involved in cognition. The function of Lrp4 in the brain, however, is unknown, as Lrp4(-/-) mice fail to form neuromuscular synapses and die at birth. Lrp4(-/-) mice, rescued for Lrp4 expression selectively in muscle, survive into adulthood and showed profound deficits in cognitive tasks that assess learning and memory. To learn whether synapses form and function aberrantly, we used electrophysiological and anatomical methods to study hippocampal CA3-CA1 synapses. In the absence of Lrp4, the organization of the hippocampus appeared normal, but the frequency of spontaneous release events and spine density on primary apical dendrites were reduced. CA3 input was unable to adequately depolarize CA1 neurons to induce long-term-potentiation. Our studies demonstrate a role for Lrp4 in hippocampal function and suggest that patients with mutations in Lrp4 or autoantibodies to Lrp4 should be evaluated for neurological deficits.