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Papers by Scott Counts

Frontiers in Neuroscience, Sep 25, 2020

The oxytocin receptor (OXTR) is a G protein-coupled receptor with a diverse repertoire of intrace... more The oxytocin receptor (OXTR) is a G protein-coupled receptor with a diverse repertoire of intracellular signaling pathways, which are activated in response to binding oxytocin (OXT) and a similar nonapeptide, vasopressin. This review summarizes the cell and molecular biology of the OXTR and its downstream signaling cascades, particularly focusing on the vasoactive functions of OXTR signaling in humans and animal models, as well as the clinical applications of OXTR targeting cerebrovascular accidents.

Alzheimer's & Dementia

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone,... more The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau‐associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD‐associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheime...

Brain Communications

The posterior cingulate cortex, a key hub of the default mode network, underlies autobiographical... more The posterior cingulate cortex, a key hub of the default mode network, underlies autobiographical memory retrieval and displays hypometabolic changes early in Alzheimer disease. To obtain an unbiased understanding of the molecular pathobiology of the aged posterior cingulate cortex, we performed RNA sequencing (RNA-seq) on tissue obtained from 26 participants of the Rush Religious Orders Study (11 males/15 females; aged 76–96 years) with a pre-mortem clinical diagnosis of no cognitive impairment and post-mortem neurofibrillary tangle Braak Stages I/II, III, and IV. Transcriptomic data were gathered using next-generation sequencing of RNA extracted from posterior cingulate cortex generating an average of 60 million paired reads per subject. Normalized expression of RNA-seq data was calculated using a global gene annotation and a microRNA profile. Differential expression (DESeq2, edgeR) using Braak staging as the comparison structure isolated genes for dimensional scaling, associative...

Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 2020

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Molecular Psychiatry, 2020

Alzheimer’s disease (AD) is the most common age-related form of dementia, associated with deposit... more Alzheimer’s disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid- β (Aβ) peptide. The p-tau tangle unit is a posttranslational modification of normal tau protein. Aβ is a neurotoxic peptide excised from the amyloid-β precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are short, single-stranded RNAs that modulate protein expression as part of the RNA-induced silencing complex (RISC). We identified miR-298 as a repressor of APP, BACE1, and the two primary forms of Aβ (Aβ40 and Aβ42) in a primary human cell culture model. Further, we discovered a novel effect of miR-298 on posttranslational levels of two specific tau moieties. Notably, miR-298 significantly reduced levels of ~55 and 50 kDa forms of the tau protein wit...

Alzheimers & Dementia, Jul 1, 2018

demand) and a-synuclein were quantified by ELISA, Von Willebrand factor (a marker of endothelial ... more demand) and a-synuclein were quantified by ELISA, Von Willebrand factor (a marker of endothelial cell content) by dot blot and a-syn-uclein also by immunohistochemistry, as in our previous studies. Choline acetyl-transferase activity was quantified by chemiluminescence. Routine neuropathological data were also available. Data was analysed using parametric statistical tests wherever possible, with the MAG:PLP ratio as the primary outcome. Results: The MAG:PLP ratio was reduced in controls compared to the dementia groups in BA18 (p¼0.034) and unchanged in BA19. There was no strong evidence of a between group difference in ChAT activity, VEGF or vWF. Conclusions: Our results do not support chronic hypoperfusion of visual processing areas in the occipital cortex as a cause of VH in those with dementia. The ChAT data require further investigation by additionally measuring AChE and BChE.

Molecular Psychiatry

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with loss of cognitive, exec... more Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with loss of cognitive, executive, and other mental functions, and is the most common form of age-related dementia. Amyloid-β peptide (Aβ) contributes to the etiology and progression of the disease. Aβ is derived from the amyloid-β precursor protein (APP). Multiple microRNA (miRNA) species are also implicated in AD. We report that human hsa-miR20b-5p (miR-20b), produced from the MIR20B gene on Chromosome X, may play complex roles in AD pathogenesis, including Aβ regulation. Specifically, miR-20b-5p miRNA levels were altered in association with disease progression in three regions of the human brain: temporal neocortex, cerebellum, and posterior cingulate cortex. In cultured human neuronal cells, miR-20b-5p treatment interfered with calcium homeostasis, neurite outgrowth, and branchpoints. A single-nucleotide polymorphism (SNP) upstream of the MIR20B gene (rs13897515) associated with differences in levels of cerebro...

Journal of Neuropathology & Experimental Neurology, 2021

Locus coeruleus (LC) neurodegeneration is associated with cognitive deterioration during the tran... more Locus coeruleus (LC) neurodegeneration is associated with cognitive deterioration during the transition from normal cognition to mild cognitive impairment (MCI) and Alzheimer disease (AD). However, the extent to which LC degenerative processes differentiate cognitively normal, “resilient” subjects bearing a high AD pathological burden from those with MCI or AD remains unclear. We approached this problem by quantifying the number of LC neurons and the percentage of LC neurons bearing AT8 tau pathology, TDP-43 pathology, or a marker for DNA/RNA oxidative damage, in well-characterized subjects diagnosed as normal cognition-low AD pathology (NC-LP), NC-high AD pathology (NC-HP), MCI, or mild/moderate AD. In addition, the severity of pontine arteriolosclerosis in each subject was compared across the groups. There was a trend for a step-wise ∼20% loss of LC neuron number between the NC-LP, NC-HP and MCI subjects despite a successive, significant ∼80%–100% increase in tau pathology between...

PLOS ONE, 2020

Background Psychological war trauma among displaced refugees is an established risk factor for me... more Background Psychological war trauma among displaced refugees is an established risk factor for mental health disorders, especially post-traumatic stress disorder (PTSD). Persons with traumainduced disorders have heightened neuroplastic restructuring of limbic brain circuits (e.g., amygdala and hippocampus), which are critical factors in the pathophysiology of PTSD. Civilians in war are exposed to both psychological trauma and environmental hazards, such as metals. Little is known about the possible mental health impact from such environmental exposures, alone or in combination with trauma. It is of special interest to determine whether war exposures contribute to dysfunctional neuroplasticity; that is, an adverse outcome from sustained stress contributing to mental health disorders. The current study examined Middle Eastern refugees in the United States to determine the relationships among pre-displacement trauma and environmental exposures, brain derived neurotrophic growth factor (BDNF) and nerve growth factor (NGF)-two neurotrophins reported to mediate neuroplasticity responses to stress-related exposures-and mental health. Methods Middle Eastern refugees (n = 64; 33 men, 31 women) from Syria (n = 40) or Iraq (n = 24) were assessed 1 month after arrival to Michigan, US. Participants were interviewed in Arabic using a semi-structured survey to assess pre-displacement trauma and environmental exposure, PTSD, depression, anxiety, and self-rated mental health. Whole blood was collected, and concentrations of six heavy metals as well as BDNF and NGF levels were determined. Because these two neurotrophins have similar functions in neuroplasticity, we

Journal of Alzheimer's Disease, 2019

Noradrenergic locus coeruleus (LC) neuron loss is a significant feature of mild cognitive impairm... more Noradrenergic locus coeruleus (LC) neuron loss is a significant feature of mild cognitive impairment and Alzheimer's disease (AD). The LC is the primary source of norepinephrine in the forebrain, where it modulates attention and memory in vulnerable cognitive regions such as prefrontal cortex (PFC) and hippocampus. Furthermore, LC-mediated norepinephrine signaling is thought to play a role in blood-brain barrier (BBB) maintenance and neurovascular coupling, suggesting that LC degeneration may impact the high comorbidity of cerebrovascular disease and AD. However, the extent to which LC projection system degeneration influences vascular pathology is not fully understood. To address this question in vivo, we stereotactically lesioned LC

Frontiers in Neuroscience, 2019

Neurobiology of disease, Jan 31, 2018

Cholinergic basal forebrain neurons of the nucleus basalis of Meynert (nbM) regulate attentional ... more Cholinergic basal forebrain neurons of the nucleus basalis of Meynert (nbM) regulate attentional and memory function and are exquisitely prone to tau pathology and neurofibrillary tangle (NFT) formation during the progression of Alzheimer's disease (AD). nbM neurons require the neurotrophin nerve growth factor (NGF), its cognate receptor TrkA, and the pan-neurotrophin receptor p75 for their maintenance and survival. Additionally, nbM neuronal activity and cholinergic tone are regulated by the expression of nicotinic (nAChR) and muscarinic (mAChR) acetylcholine receptors as well as receptors modulating glutamatergic and catecholaminergic afferent signaling. To date, the molecular and cellular relationships between the evolution of tau pathology and nbM neuronal survival remain unknown. To address this knowledge gap, we profiled cholinotrophic pathway genes within nbM neurons immunostained for pS422, a pretangle phosphorylation event preceding tau C-terminal truncation at D421, or...

Cell transplantation, Apr 13, 2017

Unscheduled cell cycle reentry of postmitotic neurons has been described in cases of mild cogniti... more Unscheduled cell cycle reentry of postmitotic neurons has been described in cases of mild cognitive impairment (MCI) and Alzheimer's disease (AD) and may form a basis for selective neuronal vulnerability during disease progression. In this regard, the multifunctional protein regulator of cell cycle (RGCC) has been implicated in driving G1/S and G2/M phase transitions through its interactions with cdc/cyclin-dependent kinase 1 (cdk1) and is induced by p53, which mediates apoptosis in neurons. We tested whether RGCC levels were dysregulated in frontal cortex samples obtained postmortem from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), MCI, or AD. RGCC mRNA and protein levels were upregulated by ∼50%-60% in MCI and AD compared to NCI, and RGCC protein levels were associated with poorer antemortem global cognitive performance in the subjects examined. To test whether RGCC might regulate neuronal cell cycle reentry and apoptosis, we differentiated neu...

Acta neuropathologica communications, Jan 21, 2017

A major feature of Alzheimer's disease (AD) is the loss of noradrenergic locus coeruleus (LC)... more A major feature of Alzheimer's disease (AD) is the loss of noradrenergic locus coeruleus (LC) projection neurons that mediate attention, memory, and arousal. However, the extent to which the LC projection system degenerates during the initial stages of AD is still under investigation. To address this question, we performed tyrosine hydroxylase (TH) immunohistochemistry and unbiased stereology of noradrenergic LC neurons in tissue harvested postmortem from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI, a putative prodromal AD stage), or mild/moderate AD. Stereologic estimates of total LC neuron number revealed a 30% loss during the transition from NCI to aMCI, with an additional 25% loss of LC neurons in AD. Decreases in noradrenergic LC neuron number were significantly associated with worsening antemortem global cognitive function as well as poorer performance on neuropsychological tests of episodic memory,...

Current Alzheimer Research, 2016

Neurobiology of Aging, 2016

Conformational phosphorylation and cleavage events drive the tau protein from a soluble, monomeri... more Conformational phosphorylation and cleavage events drive the tau protein from a soluble, monomeric state to a relatively insoluble, polymeric state that precipitates the formation of neurofibrillary tangles (NFTs) in projection neurons in Alzheimer's disease (AD), including the magnocellular perikarya located in the nucleus basal of Meynert (NBM) complex of the basal forebrain. Whether these structural changes in the tau protein are associated with pathogenic changes at the molecular and cellular level remains undetermined during the onset of AD. Here we examined alterations in gene expression within individual NBM neurons immunostained for pS422, an early tau phosphorylation event, or dual labeled for pS422 and TauC3, a later stage tau neoepitope, from tissue obtained postmortem from subjects who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. Specifically, pS422-positive pretangles displayed an upregulation of select gene transcripts subserving protein quality control. On the other hand, late stage TauC3-positive NFTs exhibited

Cellular and Molecular Life Sciences, 2008

The neuropeptide galanin and its receptors are localized in brain pathways mediating learning and... more The neuropeptide galanin and its receptors are localized in brain pathways mediating learning and memory. Central microinjection of galanin impairs performance of a variety of cognitive tasks in rats. Transgenic mice overexpressing galanin display deficits in some learning and memory tests. The inhibitory role of galanin in cognitive processes, taken together with the overexpression of galanin in Alzheimer's disease, suggests that galanin antagonists may offer a novel therapeutic approach to treat memory loss in Alzheimer's patients.

Biological Psychiatry, 2010