Narrowing down the histopathological changes in the brain after early-life exposure to general anaesthesia has presented a consistent challenge for preclinical models of anaesthetic neurotoxicity. ...Using resting-state functional magnetic resonance imaging, in this issue of the journal Neudecker and colleagues demonstrated in vivo connectivity changes in the brain following a seed-based analysis that was derived from previously reported histopathology in the same animals. The combination of neurohistology and neuroimaging should help focus future preclinical studies investigating the developmental consequences of early exposure to general anaesthesia.
Recently, AAV2.retro, a new capsid variant capable of efficient retrograde transport in brain, was generated in mice using a directed evolution approach. However, it remains unclear to what degree ...transport will be recapitulated in the substantially larger and more complex nonhuman primate (NHP) brain. Here, we compared the biodistribution of AAV2.retro with its parent serotype, AAV2, in adult macaques following delivery into the caudate and putamen, brain regions which comprise the striatum. While AAV2 transduction was primarily limited to the injected brain regions, AAV2.retro transduced cells in the striatum and in dozens of cortical and subcortical regions with known striatal afferents. We then evaluated the capability of AAV2.retro to deliver disease-related gene cargo to biologically-relevant NHP brain circuits by packaging a fragment of human mutant HTT, the causative gene mutation in Huntington's disease. Following intra-striatal delivery, pathological mHTT-positive protein aggregates were distributed widely among cognitive, motor, and limbic cortico-basal ganglia circuits. Together, these studies demonstrate strong retrograde transport of AAV2.retro in NHP brain, highlight its utility in developing novel NHP models of brain disease and suggest its potential for querying circuit function and delivering therapeutic genes in the brain, particularly where treating dysfunctional circuits, versus single brain regions, is warranted.
Inflammation has been linked to the development of nonmotor symptoms in Parkinson's disease (PD), which greatly impact patients' quality of life and can often precede motor symptoms. Suitable animal ...models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a “gold standard” model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. We report 5 cases of progressive parkinsonism in non-human primates to gain a broader understanding of MPTP-induced central and peripheral inflammatory dysfunction to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration. We measured inflammatory proteins in plasma and CSF and performed 18FFEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation. Monkeys were also evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Additionally, monkeys were treated with a novel TNF inhibitor XPro1595 (10 mg/kg, n = 3) or vehicle (n = 2) every three days starting 11 weeks after the initiation of MPTP to determine whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. The case studies revealed that earlier and robust 18FFEPPA PET signals resulted in earlier and more severe parkinsonism, which was seen in male cases compared to female cases. Potential other sex differences were observed in circulating inflammation, microbiota diversity and their metabolites. Additional studies with larger group sizes of both sexes would enable confirmation and extension of these findings. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.
Macaques are the most common nonhuman primate (NHP) species used in neuroscience research. With the advancement of many neuroimaging techniques, new studies are beginning to apply multiple types of ...in vivo magnetic resonance imaging (MRI), such as structural imaging (sMRI) with T1 and T2 weighted contrasts alongside diffusion weighed (DW) imaging. In studies involving rhesus macaques, this approach can be used to better understand micro-structural changes that occur during development, in various disease states or with normative aging. However, many of the available rhesus brain atlases have been designed for only one imaging modality, making it difficult to consistently define the same brain regions across multiple imaging modalities in the same subject. To address this, we created a brain atlas from 18 adult rhesus macaques that includes co-registered templates constructed from images frequently used to characterize macroscopic brain structure (T2/SPACE and T1/MP-RAGE), and a diffusion tensor imaging (DTI) template. The DTI template was up-sampled from 1 mm isotropic resolution to resolution match to the T1 and T2-weighted images (0.5 mm isotropic), and the parameter maps were derived for FA, AD, RD and MD.The labelmap volumes delineate 57 gray matter regions of interest (ROIs; 36 cortical regions and 21 subcortical structures), as well as 74 white matter tracts. Importantly, the labelmap overlays both the structural and diffusion templates, enabling the same regions to be consistently identified across imaging modalities. A specialized condensed version of the labelmap ROIs are also included to further extend the usefulness of this tool for imaging data with lower spatial resolution, such as functional MRI (fMRI) or positron emission tomography (PET).
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•Object and location memory was assessed in monkeys with neonatal perirhinal lesions.•Recognition of objects after delays longer than 30s was impaired.•No functional sparing after the early-onset ...perirhinal lesions.•By contrast, recognition of spatial locations was left intact.
The contribution of the perirhinal cortex (PRh) to recognition memory is well characterized in adults, yet the same lesions have limited effect on recognition of spatial locations. Here, we assessed whether the same outcomes will follow when perirhinal lesions are performed in infancy. Monkeys with neonatal perirhinal (Neo-PRh) lesions and control animals were tested in three operant recognition tasks as they reached adulthood: Delayed Nonmatching-to-Sample (DNMS) and Object Memory Span (OMS), measuring object recognition, and Spatial Memory Span (SMS), measuring recognition of spatial locations. Although Neo-PRh lesions did not impact acquisition of the DNMS rule, they did impair performance when the delays were extended from 30s to 600s. In contrast, the same neonatal lesions had no impact on either the object or spatial memory span tasks, suggesting that the lesions impacted the maintenance of information across longer delays and not memory capacity. Finally, the magnitude of recognition memory impairment after the Neo-PRh lesions was similar to that previously observed after adult-onset perirhinal lesions, indicating minimal, or no, functional compensation after the early PRh lesions. Overall, the results indicate that the PRh is a cortical structure that is important for the normal development of mechanisms supporting object recognition memory. Its contribution may be relevant to the memory impairment observed with human cases of temporal lobe epilepsy without hippocampal sclerosis, but not to the memory impairment found in developmental amnesia cases.
We created a new nonhuman primate model of the genetic neurodegenerative disorder Huntington's disease (HD) by injecting a mixture of recombinant adeno-associated viral vectors, serotypes AAV2 and ...AAV2.retro, each expressing a fragment of human mutant
(
) into the caudate and putamen of adult rhesus macaques. This modeling strategy results in expression of mutant huntingtin protein (mHTT) and aggregate formation in the injected brain regions, as well as dozens of other cortical and subcortical brain regions affected in human HD patients. We queried the disruption of cortico-basal ganglia circuitry for 30 months post-surgery using a variety of behavioral and imaging readouts. Compared to controls, mHTT-treated macaques developed working memory decline and progressive motor impairment. Multimodal imaging revealed circuit-wide white and gray matter degenerative processes in several key brain regions affected in HD. Taken together, we have developed a novel macaque model of HD that may be used to develop disease biomarkers and screen promising therapeutics.
Amyloid beta (Aβ) plaque density was examined in the amygdala of rhesus macaques, to elucidate the influence of age, diet and hormonal environment.
Luminex technology was used to measure ...cerebrospinal fluid (CSF) concentrations of Aβ
and Aβ
across three decades, while immunohistochemistry was used to examine Aβ plaque density in the amygdala.
Aβ
was found to be the predominant isoform of Aβ in the CSF, but neither Aβ
or Aβ
concentrations showed an age-related change, and the ratio of Aβ
to Aβ
showed only a marginal increase. Significantly fewer Aβ plaques were detected in the amygdala of old ovariectomized animals if they received estradiol HRT (
< 0.001); similar results were obtained regardless of whether they had been maintained on a regular monkey chow for ∼48 months or on a high-fat, high-sugar, Western-style diet for ∼30 months.
The results demonstrate that HRT involving estrogen can reduce Aβ plaque load in a cognitive brain region of aged non-human primates. The results from this translational animal model may therefore have clinical relevance to the treatment of AD in post-menopausal women, whether used alone, or as a supplement to current pharmacological and monoclonal antibody-based interventions.
The properties of the cell types that are selectively vulnerable in Huntington’s disease (HD) cortex, the nature of somatic CAG expansions of mHTT in these cells, and their importance in CNS ...circuitry have not been delineated. Here, we employed serial fluorescence-activated nuclear sorting (sFANS), deep molecular profiling, and single-nucleus RNA sequencing (snRNA-seq) of motor-cortex samples from thirteen predominantly early stage, clinically diagnosed HD donors and selected samples from cingulate, visual, insular, and prefrontal cortices to demonstrate loss of layer 5a pyramidal neurons in HD. Extensive mHTT CAG expansions occur in vulnerable layer 5a pyramidal cells, and in Betz cells, layers 6a and 6b neurons that are resilient in HD. Retrograde tracing experiments in macaque brains identify layer 5a neurons as corticostriatal pyramidal cells. We propose that enhanced somatic mHTT CAG expansion and altered synaptic function act together to cause corticostriatal disconnection and selective neuronal vulnerability in HD cerebral cortex.
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•sFANS molecular profiling of cell types in Huntington’s disease cerebral cortex•Loss of L5a corticostriatal projection neurons in Huntington’s disease•Extensive somatic CAG expansion occurs in vulnerable and resilient neurons•Gene expression analyses indicate altered synaptic function in layers 5 and 6 neurons
Vulnerable cell types in the cerebral cortex in Huntington’s disease have not been delineated completely. Pressl et al. employed sFANS and snRNA-seq to reveal that L5a corticostriatal pyramidal cells are lost early in HD progression. Molecular profiling data implicate somatic CAG expansion and altered synaptic function in HD pathogenesis.
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