Biology subjects

Baxter, M. G.

Publications and source records attributed to Baxter, M. G..

9 recordsLinked to original sources

bioRxiv2018

Disruption of the KH1 domain of Fmr1 leads to transcriptional alterations and attentional deficits in rats

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. FXS is a leading monogenic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID). In most cases, the mutation is an expansion of a microsatellite (CGG triplet), which leads to suppressed expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein involved in multiple aspects of mRNA metabolism. Interestingly, we found that the previously published Fmr1 knockout rat model of FXS expresses a transcript with an in-frame deletion of a K-homology (KH) domain, KH1. KH domains are RNA-binding domains of FMR1 and several of the few, known point mutations associated with FXS are found within them. We observed that this deletion leads to medial prefrontal cortex (mPFC)-dependent attention deficits, similar to those observed in FXS, and to alterations in transcriptional profiles within the mPFC, which mapped to two weighted gene coexpression network analysis modules. We demonstrated that these modules are conserved in human frontal cortex, are enriched for known FMRP targets and for genes involved in neuronal and synaptic processes, and that one is enriched for genes that are implicated in ASD, ID, and schizophrenia. Hub genes in these conserved modules represent potential targets for FXS. These findings provide support for a prefrontal deficit in FXS, indicate that attentional testing might be a reliable cross-species tool for investigating the pathophysiology of FXS and a potential readout for pharmacotherapy testing, and identify dysregulated gene expression modules in a relevant brain region.\n\nSignificance StatementThe significance of the current study lies in two key domains. First, this study demonstrates that deletion of the Fmrp-KH1 domain is sufficient to cause major mPFC-dependent attention deficits in both males and females, like those observed in both individuals with FXS and in knockout mouse models for FXS. Second, the study shows that deletion of the KH1 domain leads to alterations in the transcriptional profiles within the medial prefrontal cortex (mPFC), which are of potential translational value for subjects with FXS. These findings indicate that attentional testing might be a reliable cross-species tool for investigating the pathophysiology of FXS and a potential readout for pharmacotherapy testing and also highlight hub genes for follow up.

neuroscience↗

bioRxiv2018

Behavioral effect of chemogenetic inhibition is directly related to receptor transduction levels in rhesus monkeys

We used inhibitory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) to reversibly disrupt dorsolateral prefrontal cortex (dlPFC) function in male macaque monkeys. Monkeys were tested on a spatial delayed response task to assess working memory function after intramuscular injection of either clozapine-N-oxide (CNO) or vehicle. CNO injections given before DREADD transduction were without effect on behavior. rAAV5/hsyn-hM4Di-mCherry was injected bilaterally into the dlPFC of five male rhesus monkeys, to produce neuronal expression of the inhibitory (Gi-coupled) DREADD receptor. We quantified the percentage of DREADD- transduced cells using stereological analysis of mCherry-immunolabeled cells. We found a greater number of immunolabeled neurons in monkeys that displayed CNO-induced behavioral impairment after DREADD transduction compared to monkeys that showed no behavioral effect after CNO. Even in monkeys that showed reliable effects of CNO on behavior after DREADD transduction, the number of prefrontal neurons transduced with DREADD receptor was on the order of 3% of total prefrontal neurons counted. This level of histological analysis facilitates our understanding of behavioral effects, or lack thereof, after DREADD vector injection in monkeys. It also implies that a functional silencing of a relatively small fraction of dlPFC neurons, albeit in a widely distributed area, is sufficient to disrupt spatial working memory.\n\nSignificance StatementCognitive domains such as working memory and executive function are mediated by the dorsolateral prefrontal cortex (dlPFC). Impairments in these domains are common in neurodegenerative diseases as well as normal aging. The present study sought to measure deficits in a spatial delayed response task following activation of viral-vector transduced inhibitory DREADD (Designer Receptor Exclusively Activated by Designer Drug) receptors in rhesus macaques and compare this to the level of transduction in dlPFC using stereology. We found a significant relationship between the extent of DREADD transduction and the magnitude of behavioral deficit following administration of the DREADD actuator compound clozapine-N- oxide (CNO). These results demonstrate it will be critical to validate transduction to ensure DREADDs remain a powerful tool for neuronal disruption.

neuroscience↗

bioRxiv2018

The rhesus monkey hippocampus critically contributes to scene memory retrieval, but not new learning

Humans can recall a large number of memories years after the events that triggered them. Early studies of humans with amnesia led to the hippocampus being viewed as the critical structure for episodic memory, but human lesions are imprecise, making it difficult to identify the anatomical structures underlying memory impairments. Rodent studies enable great temporal and anatomical precision in hippocampal manipulations, but not investigation of the rich assortment of interleaved memories that occurs in humans. Thus it is not known how lesions restricted to the hippocampus affect the retrieval of multiple sequentially encoded memories. Furthermore, disagreement exists as to whether hippocampal inactivations lead to a temporally graded, or ungraded amnesia, which could be a consequence of different types hippocampal disruption observed in rodent and human studies. In the current study, four rhesus monkeys received bilateral neurotoxic lesions of the hippocampus, and were compared to thirteen unoperated controls on recognition and new learning of visual object-in-place scenes. Monkeys with hippocampal lesions were significantly impaired compared to controls at remembering scenes that were encoded before the lesion. We did not observe any temporal gradient effect of the lesion on memory recognition, with recent and remote memories being equally affected by the lesion. Monkeys with hippocampal lesions showed no deficits in learning and later recognising new scenes. Thus, the hippocampus, like other cortical regions, may be engaged in the acquisition and storage of new memories, but its role can be taken over by spared regions following a lesion. These findings illustrate the utility of experimental paradigms for studying retrograde and anterograde amnesia that make use of the capacity of nonhuman primates to rapidly acquire many distinct visual memories.

neuroscience↗

bioRxiv2018

Quantitative analysis of synaptic pathology and neuroinflammation: an initial study in a female rhesus monkey model of the “synaptic” phase of Alzheimer’s disease

BackgroundSoluble oligomers of the A{beta} peptide (A{beta}Os) are toxins that target and disrupt synapses. Generation of A{beta}Os has been recently recognized as a probable initiating event in Alzheimers disease (AD), leading to cognitive impairment. There is a translational gap in AD studies, with promising drugs developed based on work in rodent models failing in AD patients in clinical trials. Additionally, although women have a two-fold greater lifetime risk of developing AD compared to men, females have not been a focus of preclinical studies. Thus, we sought to develop a model of A{beta}O toxicity in female rhesus monkeys, to take advantage of the more highly differentiated cortical structure in this species as well as the similarities in the endocrine system between rhesus monkeys and humans.\n\nMethodsRepeated intracerebroventricular (i.c.v) injections of A{beta}Os were performed in adult female rhesus monkeys. Controls were unoperated aged matched monkeys. High-resolution confocal microscopy and morphometric analysis of Alexa 568 (A568) filled neurons were used to evaluate synaptic, neuronal, and glial markers in the dorsolateral prefrontal cortex (dlPFC) and hippocampus after A{beta}O injections. Cerebrospinal fluid (CSF) and brain tissue were also collected and analyzed for biomarkers of AD pathology, including: phosphorylated Tau protein (pTau), total Tau, A{beta}1-42, A{beta}1-40 and TNF- levels.\n\nResultsHere, we report that A{beta}O injection into the lateral ventricle of the brain induces loss of 37% of thin spines in targeted dlPFC neurons, an area highly vulnerable in AD and aging. Further, A{beta}Os associate with the synaptic marker PSD95, inducing loss of more than 60% of local excitatory synapses. A{beta}Os induce a robust neuroinflammatory response in the hippocampus, far from the injection site, with numerous activated ameboid microglia and TNF- release. Finally, A{beta}Os increased CSF levels of A{beta}1-42, pTau Ser396 and pTau Ser199, but not A{beta}1-40 or total Tau.\n\nConclusionsThese initial findings from detailed quantitative analysis of effects of A{beta}O administration on synapses in a female nonhuman primate model are a very promising step toward understanding the mechanism of early AD pathogenesis in the primate brain, and may help develop an effective disease-modifying therapy of high relevance to womens health.

neuroscience↗

bioRxiv2018

Timing of Cyclic Estradiol Treatment Differentially Affects Cognition in Aged Female Rhesus Monkeys

Some evidence suggests that there may be a limited \"window of opportunity\" for beneficial effects of hormone therapy on physiology after menopause in women. We tested, in aged, surgically menopausal (ovariectomized) rhesus monkeys, whether the timing of cyclic estradiol (E2) treatment impacted its effect on cognitive function. Monkeys were assigned to one of four treatment conditions after ovariectomy: either vehicle or E2 treatment for the duration of the protocol, vehicle for the first 2 years of the protocol followed by E2 for the remainder (delayed treatment), or E2 for the first year of the protocol followed by vehicle for the remainder (withdrawn treatment). Delayed treatment addressed the hypothesis that E2 treatment initiated more than 2 years after ovariectomy would have a reduced effect on cognitive function. Withdrawn treatment mirrors current clinical advice to women to use hormone therapy in the initial post-menopausal period then discontinue it. Two periods of cognitive testing assessed treatment effects on cognition over time. E2 treatment predominantly affected a prefrontal cortex-dependent test of spatiotemporal working memory (delayed response). Monkeys with delayed E2 treatment improved in delayed response performance over time, whereas vehicle-treated monkeys declined. Monkeys with withdrawn E2 treatment maintained their performance across assessments, as did monkeys treated with E2 across the entire protocol. These findings suggest that a \"window of opportunity\" for hormone treatment after cessation of ovarian function, if present in nonhuman primates, lasts longer than 2 years. It also supports the notion that beneficial effects of hormone therapy may persist after discontinuation of treatment.

neuroscience↗

bioRxiv2018

Estradiol treatment in a nonhuman primate model of menopause preserves affective reactivity

As humans age, their affective lives tend to become more positive and less negative. This phenomenon, known as the positivity effect (or positivity bias), occurs even as aging leads to declines in health and cognitive outcomes. Despite these well documented effects in humans, extent to which affective processes change in nonhuman animals, and in particular nonhuman primates - is unclear. As a first step towards developing a model for human affective aging in rhesus monkeys (Macaca mulatta), we tested aged, surgically menopausal aged and middle-aged gonadally intact female rhesus monkeys on a classic index of affective reactivity in monkeys, the Human Intruder task. The Human Intruder task evaluates behavioral responses to varying levels of threat. Aged, surgically menopausal monkeys received hormone replacement therapy consisting of a cyclic estradiol regimen, or vehicle injections as a control. Average responsivity to threat did not vary by condition, but middle aged monkeys and aged monkeys on estradiol were more reactive to the most potent level of threat than to a moderate level of threat, replicating previously published results in other age groups and male monkeys. In contrast, aged monkeys not on estradiol did not show such calibration to threat level. These findings suggest that estrogen may be important for maintaining more youthful affective responding. They also illustrate the utility of behavioral assays of affective reactivity in nonhuman primate models of cognitive and reproductive aging in humans.

animal behavior and cognition↗

bioRxiv2017

An open resource for nonhuman primate imaging

Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience.\n\nUnfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMate Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 13 independent data collections aggregated across 11 sites (total = 98 macaque monkeys). We also outline the unique pitfalls and challenges that should be considered in the analysis of the non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets.

neuroscience↗

bioRxiv2017

Lack of evidence for sex differences in higher cognitive function in macaques

Here we assessed whether higher cognitive function differed between male and female rhesus monkeys using tests of episodic memory and strategy implementation. We did not find any difference between males and females on behavioral performance or on analyses of grey matter volume of key regions. Our findings suggest that, at least where higher cognitive function in healthy monkeys is concerned, the sexes may not differ.

neuroscience↗

bioRxiv2017

A Theta Band Network Involving Prefrontal Cortex Unique To Human Episodic Memory

Episodic memory, everyday memory for events, is fundamental to our lives. We tested patients undergoing intracranial electroencephalography (intracranial EEG) monitoring for the localization of medically-refractory epilepsy on a well-characterized paradigm that requires episodic memory. Here we report that an anatomically diffuse network characterized by thetaband (4-7 Hz) coherence is activated at the time of a choice that requires episodic memory. This distinct network pattern of oscillatory activity is absent in situations that do not require episodic memory. The episodic network we identified spans prefrontal and temporal lobes and coherence between these areas was greatest during memory encoding. Our data provide novel empirical evidence for a set of brain areas that supports episodic memory in humans.\n\nSignificance StatementSynchronous oscillations of electrical fields are thought to support brain processes such as language, movement, memory and learning. However, little is known about which types of synchronous oscillations are needed for which process. We performed invasive recordings of electrical activity in patients undergoing surgical management for epilepsy while they perform different types of memory tasks. We found synchronous oscillations in the theta band (4-7 Hz) correlate with performance in an episodic memory. This pattern of oscillations activates a distinct network of brain regions from a task that does not require episodic memory. This finding advances our understanding of the brain systems that support each process.

neuroscience↗