Temporally precise population coding of dynamic sounds by auditory cortex.

Fluctuations in the amplitude envelope of complex sounds provide critical cues for hearing, particularly for speech and animal vocalizations. Responses to amplitude modulation (AM) in the ascending auditory pathway have chiefly been described for single neurons. How neural populations might collectively encode and represent information about AM remains poorly characterized, even in primary auditory cortex (A1). We modeled population responses to AM based on data recorded from A1 neurons in awake squirrel monkeys and evaluated how accurately single trial responses to modulation frequencies from 4 to 512 Hz could be decoded as functions of population size, composition, and correlation structure. We found that a population-based decoding model that simulated convergent, equally weighted inputs was highly accurate and remarkably robust to the inclusion of neurons that were individually poor decoders. By contrast, average rate codes based on convergence performed poorly; effective decoding using average rates was only possible when the responses of individual neurons were segregated, as in classical population decoding models using labeled lines. The relative effectiveness of dynamic rate coding in auditory cortex was explained by shared modulation phase preferences among cortical neurons, despite heterogeneity in rate-based modulation frequency tuning. Our results indicate significant population-based synchrony in primary auditory cortex and suggest that robust population coding of the sound envelope information present in animal vocalizations and speech can be reliably achieved even with indiscriminate pooling of cortical responses. These findings highlight the importance of firing rate dynamics in population-based sensory coding.NEW & NOTEWORTHY Fundamental questions remain about population coding in primary auditory cortex (A1). In particular, issues of spike timing in models of neural populations have been largely ignored. We find that spike-timing in response to sound envelope fluctuations is highly similar across neuron populations in A1. This property of shared envelope phase preference allows for a simple population model involving unweighted convergence of neuronal responses to classify amplitude modulation frequencies with high accuracy.

Transcription factor Sp1 inhibition, memory, and cytokines in a mouse model of Alzheimer's disease.

Transcription factors are involved to varying extents in the health and survival of neurons in the brain and a better understanding of their roles with respect to the pathogenesis of Alzheimer's disease (AD) could lead to the development of additional treatment strategies. Sp1 is a transcription factor that responds to inflammatory signals occurring in the AD brain. It is known to regulate genes with demonstrated importance in AD, and we have previously found it upregulated in the AD brain and in brains of transgenic AD model mice. To better understand the role of Sp1 in AD, we tested whether we could affect memory function (measured with a battery of behavioral tests discriminating different aspects of cognitive function) in a transgenic model of AD by pharmaceutical modulation of Sp1. We found that inhibition of Sp1 function in transgenic AD model mice increased memory deficits, while there were no changes in sensorimotor or anxiety tests. Aß42 and Aß40 peptide levels were significantly higher in the treated mice, indicating that Sp1 elevation in AD could be a functionally protective response. Circulating levels of CXCL1 (KC) decreased following treatment with mithramycin, while a battery of other cytokines, including IL-1α, IL-6, INF-γ and MCP-1, were unchanged. Gene expression levels for several genes important to neuronal health were determined by qRT-PCR, and none of these appeared to change at the transcriptional level.

Acetylcholine functionally reorganizes neocortical microcircuits.

Sensory information is processed and transmitted through the synaptic structure of local cortical circuits, but it is unclear how modulation of this architecture influences the cortical representation of sensory stimuli. Acetylcholine (ACh) promotes attention and arousal and is thought to increase the signal-to-noise ratio of sensory input in primary sensory cortices. Using high-speed two-photon calcium imaging in a thalamocortical somatosensory slice preparation, we recorded action potential activity of up to 900 neurons simultaneously and compared local cortical circuit activations with and without bath presence of ACh. We found that ACh reduced weak pairwise relationships and excluded neurons that were already unreliable during circuit activity. Using action potential activity from the imaged population, we generated functional wiring diagrams based on the statistical dependencies of activity between neurons. ACh pruned weak functional connections from spontaneous circuit activations and yielded a more modular and hierarchical circuit structure, which biased activity to flow in a more feedforward fashion. Neurons that were active in response to thalamic input had reduced pairwise dependencies overall, but strong correlations were conserved. This coincided with a prolonged period during which neurons showed temporally precise responses to thalamic input. Our results demonstrate that ACh reorganizes functional circuit structure in a manner that may enhance the integration and discriminability of thalamic afferent input within local neocortical circuitry.

GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice.

Rheumatoid arthritis (RA) is a negative risk factor for the development of Alzheimer's disease (AD). While it has been commonly assumed that RA patients' usage of non-steroidal anti-inflammatory drugs (NSAIDs) helped prevent onset and progression of AD, NSAID clinical trials have proven unsuccessful in AD patients. To determine whether intrinsic factors within RA pathogenesis itself may underlie RA's protective effect, we investigated the activity of colony-stimulating factors, upregulated in RA, on the pathology and behavior of transgenic AD mice. 5 microg bolus injections of macrophage, granulocyte, and granulocyte-macrophage colony-stimulating factors (M-CSF, G-CSF, or GM-CSF) were administered unilaterally into the hippocampus of aged cognitively-impaired AD mice and the resulting amyloid load reductions determined one week later, using the artificial cerebrospinal fluid-injected contralateral sides as controls. G-CSF and more significantly, GM-CSF reduced amyloidosis throughout the treated brain hemisphere one week following bolus administration to AD mice. 20 daily subcutaneous injections of 5 microg of GM-CSF (the most amyloid-reducing CSF in the bolus experiment) were administered to balanced cohorts of AD mice after assessment in a battery of cognitive tests. Reductions in amyloid load and improvements in cognitive function were assessed. Subcutaneous GM-CSF administration significantly reduced brain amyloidosis and completely reversed the cognitive impairment, while increasing hippocampal synaptic area and microglial density. These findings, along with two decades of accrued safety data using Leukine, recombinant human GMCSF, in elderly leukopenic patients, suggest that Leukine should be tested as a treatment to reverse cerebral amyloid pathology and cognitive impairment in AD.

Electromagnetic field treatment protects against and reverses cognitive impairment in Alzheimer's disease mice.

Despite numerous studies, there is no definitive evidence that high-frequency electromagnetic field (EMF) exposure is a risk to human health. To the contrary, this report presents the first evidence that long-term EMF exposure directly associated with cell phone use (918 MHz; 0.25 w/kg) provides cognitive benefits. Both cognitive-protective and cognitive-enhancing effects of EMF exposure were discovered for both normal mice and transgenic mice destined to develop Alzheimer's-like cognitive impairment. The cognitive interference task utilized in this study was designed from, and measure-for-measure analogous to, a human cognitive interference task. In Alzheimer's disease mice, long-term EMF exposure reduced brain amyloid-beta (Abeta) deposition through Abeta anti-aggregation actions and increased brain temperature during exposure periods. Several inter-related mechanisms of EMF action are proposed, including increased Abeta clearance from the brains of Alzheimer's disease mice, increased neuronal activity, and increased cerebral blood flow. Although caution should be taken in extrapolating these mouse studies to humans, we conclude that EMF exposure may represent a non-invasive, non-pharmacologic therapeutic against Alzheimer's disease and an effective memory-enhancing approach in general.

Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice.

We have recently shown that Alzheimer's disease (AD) transgenic mice given a moderate level of caffeine intake (the human equivalent of 5 cups of coffee per day) are protected from development of otherwise certain cognitive impairment and have decreased hippocampal amyloid-beta (Abeta) levels due to suppression of both beta-secretase (BACE1) and presenilin 1 (PS1)/gamma-secretase expression. To determine if caffeine intake can have beneficial effects in "aged" APPsw mice already demonstrating cognitive impairment, we administered caffeine in the drinking water of 18-19 month old APPsw mice that were impaired in working memory. At 4-5 weeks into caffeine treatment, those impaired transgenic mice given caffeine (Tg/Caff) exhibited vastly superior working memory compared to the continuing impairment of control transgenic mice. In addition, Tg/Caff mice had substantially reduced Abeta deposition in hippocampus (decrease 40%) and entorhinal cortex (decrease 46%), as well as correlated decreases in brain soluble Abeta levels. Mechanistically, evidence is provided that caffeine suppression of BACE1 involves the cRaf-1/NFkappaB pathway. We also determined that caffeine concentrations within human physiological range effectively reduce active and total glycogen synthase kinase 3 levels in SweAPP N2a cells. Even with pre-existing and substantial Abeta burden, aged APPsw mice exhibited memory restoration and reversal of AD pathology, suggesting a treatment potential of caffeine in cases of established AD.

Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease.

The neurohormone melatonin has been reported to exert anti-beta-amyloid aggregation, antioxidant, and anti-inflammatory actions in various in vitro and animal models. To comprehensively determine the potential for long-term melatonin treatment to protect Alzheimer's transgenic mice against cognitive impairment and development of beta-amyloid (Abeta) neuropathology, we administered melatonin (100 mg/L drinking water) to APP + PS1 double transgenic (Tg) mice from 2-2.5 months of age to their killing at age 7.5 months. A comprehensive behavioral battery administered during the final 6 weeks of treatment revealed that Tg mice given melatonin were protected from cognitive impairment in a variety of tasks of working memory, spatial reference learning/memory, and basic mnemonic function; Tg control mice remained impaired in all of these cognitive tasks/domains. Immunoreactive Abeta deposition was significantly reduced in hippocampus (43%) and entorhinal cortex (37%) of melatonin-treated Tg mice. Although soluble and oligomeric forms of Abeta1-40 and 1-42 were unchanged in the hippocampus and cortex of the same melatonin-treated Tg mice, their plasma Abeta levels were elevated. These Abeta results, together with our concurrent demonstration that melatonin suppresses Abeta aggregation in brain homogenates, are consistent with a melatonin-facilitated removal of Abeta from the brain. Inflammatory cytokines such as tumor necrosis factor (TNF)-alpha were decreased in hippocampus (but not plasma) of Tg+ melatonin mice. Finally, the cortical mRNA expression of three antioxidant enzymes (SOD-1, glutathione peroxidase, and catalase) was significantly reduced to non-Tg levels by long-term melatonin treatment in Tg mice. Thus, melatonin's cognitive benefits could involve its anti-Abeta aggregation, anti-inflammatory, and/or antioxidant properties. Our findings provide support for long-term melatonin therapy as a primary or complementary strategy for abating the progression of Alzheimer disease.

Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice.

We previously reported that intraperitoneal (i.p.) injection (20 mg/kg) of (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, decreased beta-amyloid (Abeta) levels and plaques via promotion of the non-amyloidogenic alpha-secretase proteolytic pathway in "Swedish" mutant amyloid precursor protein overexpressing (APPsw, Tg) mice. Here, we find that EGCG administered orally in drinking water (50 mg/kg) similarly reduces Abeta deposition in these mice. Following a six month treatment of an 8 month old cohort, immunohistochemical analysis of coronal sections reveals that plaque burdens were reduced in the cingulate cortex, hippocampus, and entorhinal cortex by 54%, 43%, and 51%, respectively. Congo red plaque burdens were decreased in the cingulate cortex, hippocampus, and entorhinal cortex by 53%, 53%, and 58%, respectively as well. ELISA of brain homogenates of the treatment Tg mice revealed consistent reductions in both Abeta1-40 and 1-42 soluble and insoluble forms. In the present study we also investigated the effect EGCG administration had on tau pathology and cognition in Tg mice. Both i.p. and orally-treated Tg animals were found to have modulated tau profiles, with markedly suppressed sarkosyl-soluble phosphorylated tau isoforms. Radial arm water maze (RAWM) testing for working memory indicated that EGCG provided cognitive benefit to Tg mice with both i.p. and oral administration, although i.p.-treated animals showed a more pronounced benefit because of the greater impairment of their Tg controls at the time of testing. Taken together, these data further the notion of EGCG dietary supplementation as a potentially safe and effective prophylaxis for Alzheimer's disease.

Use of artificial neural networks to determine cognitive impairment and therapeutic effectiveness in Alzheimer's transgenic mice.

Behavioral testing of transgenic mouse models of Alzheimer's disease (AD) is the functional endpoint for determining the effectiveness of therapeutic interventions and elucidating AD pathogenesis. Utilizing these mouse models, there have been remarkably few attempts to analyze multiple behavioral measures/tasks with higher-level computation techniques, either to distinguish performance between transgenic groups or to reveal any "overall" cognitive benefit of a given therapeutic. The present study compared the classificatory accuracy of artificial neural networks (ANNs) versus more traditional discriminant function analysis (DFA) using multiple behavioral measures/tasks from two AD transgenic mouse investigations. These investigations were to determine if AD transgenic mice could be cognitively-protected by either long-term caffeine administration (CA) or by a cognitively-stimulating environment (SE). Both the entire set of behavioral measures and a subset of 8 cognitive-based measures were analyzed. Both classifiers revealed a beneficial "overall" effect of CA and SE to protect AD transgenic mice across multiple cognitive measures/tasks. However, for both CA and SE datasets, the ANN was superior to DFA for discerning transgenicity (non-transgenic vs. transgenic-controls) across multiple behavioral measures. These results indicate that ANNs have an excellent capacity to discriminate cognitive impairment in AD transgenic mice and thus designate ANNs as a novel, sensitive method for cognitive assessment in Alzheimer's research.

Abeta-specific T-cells reverse cognitive decline and synaptic loss in Alzheimer's mice.

Active and passive Abeta immunotherapy provide behavioral benefits in AD transgenic mice, but they can also induce adverse immune over-activation and neuropathological effects. Here, we show that a restricted Abeta-specific immune re-activation can provide cognitive and pathological benefits to APPsw + PS1 transgenic mice for at least 2 1/2 months. A single infusion of Abeta-specific immune cells from Abeta-vaccinated littermates improved performance in cognitively impaired APP + PS1 mice. Recipients had lower levels of soluble Abeta in the hippocampus, less plaque-associated microglia, and more intense synaptophysin immunoreactivity, compared with untreated controls. However, Abeta-specific infusates enriched for Th1 or depleted of CD4(+) T-cells were not effective, nor were ovalbumin-specific infusates. These benefits occurred without global or brain-specific inflammatory responses. Chronically high levels of Abeta can cause immune tolerance, hypo-responsiveness, or anergy to Abeta, but our findings demonstrate that Abeta-specific immune cells can resume endogenous Abeta-lowering processes and may be an effective Abeta therapeutic.