Selective Neuronal Vulnerability Research Articles

Optogenetic Phase Transition of TDP-43 in Spinal Motor Neurons of Zebrafish Larvae.

Abnormal protein aggregation and selective neuronal vulnerability are two major hallmarks of neurodegenerative diseases. Causal relationships between these features may be interrogated by controlling the phase transition of a disease-associated protein in a vulnerable cell type, although this experimental approach has been limited so far. Here, we describe a protocol to induce phase transition of the RNA/DNA-binding protein TDP-43 in spinal motor neurons of zebrafish larvae for modeling cytoplasmic aggregation of TDP-43 occurring in degenerating motor neurons in amyotrophic lateral sclerosis (ALS). We describe a bacterial artificial chromosome (BAC)-based genetic method to deliver an optogenetic TDP-43 variant selectively to spinal motor neurons of zebrafish. The high translucency of zebrafish larvae allows for the phase transition of the optogenetic TDP-43 in the spinal motor neurons by a simple external illumination using a light-emitting diode (LED) against unrestrained fish. We also present a basic workflow of live imaging of the zebrafish spinal motor neurons and image analysis with freely available Fiji/ImageJ software to characterize responses of the optogenetic TDP-43 to the light illumination. This protocol enables the characterization of TDP-43 phase transition and aggregate formation in an ALS-vulnerable cellular environment, which should facilitate an investigation of its cellular and behavioral consequences.

CAV2.3 expression is upregulated in the substantia nigra pars compacta of humans with Parkinson's disease

• Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is responsible for motor symptoms of Parkinson's disease. • R-type calcium channels have been linked to selective vulnerability of the nigral neurons in an animal model of Parkinson's disease. • Immunohistochemistry was used to examine CAV2.3 expression in human brains. • In Parkinson's disease patients the nigral expression of CAV2.3 was higher than those of the neighbouring ventral tegmental area and control brains. • R-type calcium channels might be therapeutic targets for Parkinson's disease.

The Cerebellum in Niemann-Pick C1 Disease: Mouse Versus Man.

Selective neuronal vulnerability is common to most degenerative disorders, including Niemann-Pick C (NPC), a rare genetic disease with altered intracellular trafficking of cholesterol. Purkinje cell dysfunction and loss are responsible for cerebellar ataxia, which is among the prevailing neurological signs of the NPC disease. In this review, we focus on some questions that are still unresolved. First, we frame the cerebellar vulnerability in the context of the extended postnatal time length by which the development of this structure is completed in mammals. In line with this thought, the much later development of cerebellar symptoms in humans is due to the later development and/or maturation of the cerebellum. Hence, the occurrence of developmental events under a protracted condition of defective intracellular cholesterol mobilization hits the functional maturation of the various cell types generating the ground of increased vulnerability. This is particularly consistent with the high cholesterol demand required for cell proliferation, migration, differentiation, and synapse formation/remodeling. Other major questions we address are why the progression of Purkinje cells loss is always from the anterior to the posterior lobes and why cerebellar defects persist in the mouse model even when genetic manipulations can lead to nearly normal survival.

Neuroinflammation: 2022 update.

Besides important progress in the understanding of the pathological substrate of COVID-19-associated brain disease, major insights into mechanisms of neurodegeneration in human disease have been provided in neuropathological studies published in 2021. Recently developed techniques, which allow the simultaneous detection of a large battery of different molecules within single cells, have proven useful in the analysis of disease mechanisms in experimental and human neuroinflammatory conditions. They have elucidated protective and detrimental effects of activated microglia, which act in a stage and context-dependent manner in the induction and propagation of neurodegeneration. In addition, they emphasize the importance of synaptic damage and of selective neuronal vulnerability in the respective diseases. The results provide important new insights with high clinical relevance.

2021 marks a new era for Alzheimer's therapeutics

2021 marks a new era for Alzheimer's therapeutics

Early Thalamic Injury After Resuscitation From Severe Asphyxial Cardiac Arrest in Developing Rats.

Children who survive cardiac arrest often develop debilitating sensorimotor and cognitive deficits. In animal models of cardiac arrest, delayed neuronal death in the hippocampal CA1 region has served as a fruitful paradigm for investigating mechanisms of injury and neuroprotection. Cardiac arrest in humans, however, is more prolonged than in most experimental models. Consequently, neurologic deficits in cardiac arrest survivors arise from injury not solely to CA1 but to multiple vulnerable brain structures. Here, we develop a rat model of prolonged pediatric asphyxial cardiac arrest and resuscitation, which better approximates arrest characteristics and injury severity in children. Using this model, we characterize features of microglial activation and neuronal degeneration in the thalamus 24 h after resuscitation from 11 and 12 min long cardiac arrest. In addition, we test the effect of mild hypothermia to 34°C for 8 h after 12.5 min of arrest. Microglial activation and neuronal degeneration are most prominent in the thalamic Reticular Nucleus (nRT). The severity of injury increases with increasing arrest duration, leading to frank loss of nRT neurons at longer arrest times. Hypothermia does not prevent nRT injury. Interestingly, injury occurs selectively in intermediate and posterior nRT segments while sparing the anterior segment. Since all nRT segments consist exclusively of GABA-ergic neurons, we asked if GABA-ergic neurons in general are more susceptible to hypoxic-ischemic injury. Surprisingly, cortical GABA-ergic neurons, like their counterparts in the anterior nRT segment, do not degenerate in this model. Hence, we propose that GABA-ergic identity alone is not sufficient to explain selective vulnerability of intermediate and posterior nRT neurons to hypoxic-ischemic injury after cardiac arrest and resuscitation. Our current findings align the animal model of pediatric cardiac arrest with human data and suggest novel mechanisms of selective vulnerability to hypoxic-ischemic injury among thalamic GABA-ergic neurons.

Cannabinoid agonist WIN 55,212‐2 improves memory consolidation in a rat model of basal forebrain cholinergic lesion

AbstractBackgroundAlzheimer’s disease (AD) is associated with a selective vulnerability of basal forebrain cholinergic neurons (BFCN). The endocannabinoid (eCB) system modulates those BFCN pathways in AD. However, the effect of cannabinoid compounds on memory and learning remains controversial. Therefore, we evaluate the effect of cannabinoid agonists in recognition learning and memory in rats with a specific lesion of BFCN.MethodSprague‐Dawley male rats were infused bilaterally in the BFCN with 192IgG‐saporin toxin, (SAP group, n=10). Another group of SAP rats was treated with CB1 receptor agonist WIN 55,212‐2 for 5 days (SAP+WIN, n=10). Memory and learning were evaluated by Novel Object Recognition Task (NORT). The ability to identify new objects in the short term (3h after learning) and the long term (24h after learning), and other exploratory parameters, were measured.ResultIn the short term, control group and SAP group spent significantly more time exploring the new object than the old one (CON: 68.37% ± 4.05, p>0.01 and SAP: 60.72% ± 2.86, p>0.01), while SAP+WIN group did not (50.42% ± 5.73). In the long term, control group spent significantly more time exploring the new object than the old one (70.81% ± 2.42, p>0.001), but SAP group failed to do so (54.85% ± 3.93). Interestingly, SAP+WIN rats also spent more time exploring the new object than the old one (60.37% ± 6.36, p>0.05). Moreover, SAP group showed an increased exploratory behavior compared to control group, measured by the total exploration time in the long term (SAP: 49.76s ± 5.36 vs CON: 26.51s ± 4.45, p>0.05) and the number of rearings performed (SAP: 30.5 ± 2.4 vs CON: 21.3 ± 2.3, p>0.05). WIN 55,212‐2 treatment did not modify these latter parameters.ConclusionThese results suggest that degeneration of BFCN pathways does not impair learning in NORT test, but impairs memory consolidation. A sub‐chronic treatment with WIN 55,212‐2 was able to restore memory in rats with a BFCN lesion, even if it induces attention deficits at the short term. Thus, we suggest that cannabinoid agonists might be a plausible treatment for the typical contextual recognition problems derived from BFCN impairment in AD patients.

Pathological correlates of clinical heterogeneity in Alzheimer's disease

AbstractBackgroundAtypical variants of Alzheimer's Disease (AD) manifest predominantly with non‐memory complaints, including visuospatial (posterior cortical atrophy), language (logopenic variant of primary progressive aphasia), motor (cortico‐basal syndrome), executive or cognitive‐behavioral patterns. Compared to typical (amnestic) AD, these atypical profiles are characterized by faster cognitive decline rates, syndrome‐specific atrophy patterns, younger age at onset, and tend to be less associated with apolipoprotein E (APOE) ɛ4 allele genotype.Despite clinical differences, both typical AD and atypical AD variants feature deposits of amyloid plaques and neurofibrillary tangles and can be staged using the same neuropathological guidelines. Although it is clear that AD atypical phenotypes presented different atrophy and hypometabolism patterns among themselves and compared to typical AD, it is unclear what is the neuropathological subtract underlying an atypical AD presentation. Our work, supported by the literature, suggests that the regional pattern of plaque accumulation in advanced disease is not distinctive in each of the clinical variants of AD. Conversely, cumulative evidence from neuropathology and neuroimaging studies suggests that variations in the regional tau burden are closely related to the expression of AD's clinical variants.MethodThis presentation will review published and unpublished evidence from human neuropathological studies addressing the neurobiological substrates atypical AD variantsResultIt will include a discussion on similarities and differences in plaque and tangle burden, neuropathological comorbidities. We will also present unpublished results from a systematic study with over 140 AD cases (35% atypical) showing that comorbid pathologies do not play an essential role in determining atypical ADConclusionFinally, it will discuss the role of distinct mechanisms of selective neuronal vulnerability in concern with atypical AD.

Multi-omic analysis of selectively vulnerable motor neuron subtypes implicates altered lipid metabolism in ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating disorder in which motor neurons degenerate, the causes of which remain unclear. In particular, the basis for selective vulnerability of spinal motor neurons (sMNs) and resistance of ocular motor neurons (oMNs) to degeneration in ALS has yet to be elucidated. Here, we applied comparative multi-omics analysis of human induced pluripotent stem cell (hiPSC)-derived sMNs and oMNs to identify shared metabolic perturbations in inherited and sporadic ALS sMNs, revealing dysregulation in lipid metabolism and its related genes. Targeted metabolomics studies confirmed such findings in sMNs of 17 ALS (SOD1, C9ORF72, TDP43 and sporadic) hiPSC lines, identifying elevated levels of arachidonic acid (AA). Pharmacological reduction of AA levels was sufficient to reverse ALS-related phenotypes in both human sMNs and in vivo in Drosophila and SOD1G93A mouse models. Collectively, these findings pinpoint a catalytic step of lipid metabolism as a potential therapeutic target for ALS.

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration.

Multiple neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are being suggested to have common cellular and molecular pathological mechanisms, characterized mainly by protein misfolding and aggregation. These large inclusions, most likely, represent an end stage of a molecular cascade; however, the soluble misfolded proteins, which take part in earlier steps of this cascade, are the more toxic players. These pathological proteins, which characterize each specific disease, lead to the selective vulnerability of different neurons, likely resulting from a combination of different intracellular mechanisms, including mitochondrial dysfunction, ER stress, proteasome inhibition, excitotoxicity, oxidative damage, defects in nucleocytoplasmic transport, defective axonal transport and neuroinflammation. Damage within these neurons is enhanced by damage from the nonneuronal cells, via inflammatory processes that accelerate the progression of these diseases. In this review, while acknowledging the hallmark proteins which characterize the most common NDDs; we place specific focus on the common overlapping mechanisms leading to disease pathology despite these different molecular players and discuss how this convergence may occur, with the ultimate hope that therapies effective in one disease may successfully translate to another.

Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease

Huntington disease (HD) is a fatal neurodegenerative movement disorder caused by an expanded CAG repeat in the huntingtin gene (HTT). The mutant huntingtin protein is ubiquitously expressed, but only certain brain regions are affected. The hypothalamus has emerged as an important area of pathology with selective loss of neurons expressing the neuropeptides orexin (hypocretin), oxytocin and vasopressin in human postmortem HD tissue. Hypothalamic changes in HD may have implications for early disease manifestations affecting the regulation of sleep, emotions and metabolism. The underlying mechanisms of selective vulnerability of certain neurons in HD are not fully understood, but excitotoxicity has been proposed to play a role. Further understanding of mechanisms rendering neurons sensitive to mutant huntingtin may reveal novel targets for therapeutic interventions. In the present study, we wanted to examine whether transgenic HD mice display altered sensitivity to excitotoxicity in the hypothalamus. We first assessed effects of hypothalamic injections of the excitotoxin quinolinic acid (QA) into wild-type (WT) mice. We show that neuronal populations expressing melanin-concentrating hormone (MCH) and cocaine and amphetamine-regulated transcript (CART) display a dose-dependent sensitivity to QA. In contrast, neuronal populations expressing orexin, oxytocin, vasopressin as well as tyrosine hydroxylase in the A13 area are resistant to QA-induced toxicity. We demonstrate that the R6/2 transgenic mouse model expressing a short fragment of mutant HTT displays hypothalamic neuropathology with discrete loss of the neuronal populations expressing orexin, MCH, CART, and orexin at 12 weeks of age. The BACHD mouse model expressing full-length mutant HTT does not display any hypothalamic neuropathology at 2 months of age. There was no effect of hypothalamic injections of QA on the neuronal populations expressing orexin, MCH, CART or oxytocin in neither HD mouse model. In conclusion, we find no support for a role of excitotoxicity in the loss of hypothalamic neuronal populations in HD.

Selective Neuron Vulnerability in Common and Rare Diseases-Mitochondria in the Focus.

Mitochondrial dysfunction is a central feature of neurodegeneration within the central and peripheral nervous system, highlighting a strong dependence on proper mitochondrial function of neurons with especially high energy consumptions. The fitness of mitochondria critically depends on preservation of distinct processes, including the maintenance of their own genome, mitochondrial dynamics, quality control, and Ca2+ handling. These processes appear to be differently affected in common neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, as well as in rare neurological disorders, including Huntington’s disease, Amyotrophic Lateral Sclerosis and peripheral neuropathies. Strikingly, particular neuron populations of different morphology and function perish in these diseases, suggesting that cell-type specific factors contribute to the vulnerability to distinct mitochondrial defects. Here we review the disruption of mitochondrial processes in common as well as in rare neurological disorders and its impact on selective neurodegeneration. Understanding discrepancies and commonalities regarding mitochondrial dysfunction as well as individual neuronal demands will help to design new targets and to make use of already established treatments in order to improve treatment of these diseases.

Killing ageing neurons, one cell at a time.

In neurodegenerative diseases, certain types of neurons perish first, but the mechanisms of this selective neuronal vulnerability remain unclear. A new study now highlights a crucial role for apolipoprotein E in driving neuronal death in both ageing and Alzheimer’s disease.

Global Neurotoxicity: Quantitative Analysis of Rat Brain Toxicity Following Exposure to Trimethyltin.

The organotin, trimethyltin (TMT), is a highly toxic compound. In this study, silver-stained rat brain sections were qualitatively and quantitatively evaluated for degeneration after systemic treatment with TMT. Degenerated neurons were counted using image analysis methods available in the HALO image analysis software. Specific brain areas including the cortex, inferior and superior colliculus, and thalamus were quantitatively analyzed. Our results indicate extensive and widespread damage to the rat brain after systemic administration of TMT. Qualitative results suggest severe TMT-induced toxicity 3 and 7 days after the administration of TMT. Trimethyltin toxicity was greatest in the hippocampus, olfactory area, cerebellum, pons, mammillary nucleus, inferior and superior colliculus, hypoglossal nucleus, thalamus, and cerebellar Purkinje cells. Quantification showed that the optic layer of the superior colliculus exhibited significantly more degeneration compared to layers above and below. The inferior colliculus showed greater degeneration in the dorsal area relative to the central area. Similarly, in cortical layers, there was greater neurodegeneration in deeper layers compared to superficial layers. Quantification of damage in various thalamic nuclei showed that the greatest degeneration occurred in midline and intralaminar nuclei. These results suggest selective neuronal network vulnerability to TMT-related toxicity in the rat brain.

Multi-OMICS study of a CHCHD10 variant causing ALS demonstrates metabolic rewiring and activation of endoplasmic reticulum and mitochondrial unfolded protein responses.

Mutations in CHCHD10, coding for a mitochondrial intermembrane space protein, are a rare cause of autosomal dominant amyotrophic lateral sclerosis. Mutation-specific toxic gain of function or haploinsufficiency models have been proposed to explain pathogenicity. To decipher the metabolic dysfunction associated with the haploinsufficient p.R15L variant, we integrated transcriptomic, metabolomic and proteomic data sets in patient cells subjected to an energetic stress that forces the cells to rely on oxidative phosphorylation for ATP production. Patient cells had a complex I deficiency that resulted in an increased NADH/NAD+ ratio, diminished TCA cycle activity, a reorganization of one carbon metabolism and an increased AMP/ATP ratio leading to phosphorylation of AMPK and inhibition of mTORC1. These metabolic changes activated the unfolded protein response (UPR) in the ER through the IRE1/XBP1 pathway, upregulating downstream targets including ATF3, ATF4, CHOP and EGLN3, and two cytokine markers of mitochondrial disease, GDF15 and FGF21. Activation of the mitochondrial UPR was mediated through an upregulation of the transcription factors ATF4 and ATF5, leading to increased expression of mitochondrial proteases and heat shock proteins. There was a striking transcriptional up regulation of at least seven dual specific phosphatases, associated with an almost complete dephosphorylation of JNK isoforms, suggesting a concerted deactivation of MAP kinase pathways. This study demonstrates that loss of CHCHD10 function elicits an energy deficit that activates unique responses to nutrient stress in both the mitochondria and ER, which may contribute to the selective vulnerability of motor neurons.

Deepen into sleep and wake patterns across Alzheimer's disease phenotypes.

Although, the clinical variants of Alzheimer's disease (AD) show distinct patterns of cognitive and behavioral decline, disease progression, and neuropathological features, it is unclear if this clinical heterogeneity extends to sleep-wake patterns. Sleep and wake disturbances are frequent in typical AD, often preceding memory loss and negatively impacting the quality of life of patients and caregivers alike. Still, sleep and wake disorders are often misdiagnosed and undertreated in typical AD. Better characterization of sleep-wake features in AD clinical variants is an unmet gap of high importance because these differing patterns may require tailored treatment strategies. Moreover, as wake-promoting neurons are located in subcortical nuclei and degenerate early in typical AD, contrasting the profiles of sleep-wake patterns in typical and atypical AD aids diagnosis and brings a unique opportunity to uncover the mechanisms underlying AD clinical variants at the subcortical level and mechanisms for selective neuronal vulnerability.

Chapter 10 - Spatial topography of the basal forebrain cholinergic projections: Organization and vulnerability to degeneration

The basal forebrain (BF) cholinergic system constitutes a heterogeneous cluster of large projection neurons that innervate the entire cortical mantle and amygdala. Cholinergic neuromodulation plays a critical role in regulating cognition and behavior, as well as maintenance of cellular homeostasis. Decades of postmortem histology research have demonstrated that the BF cholinergic neurons are selectively vulnerable to aging and age-related neuropathology in degenerative diseases such as Alzheimer's and Parkinson's diseases. Emerging evidence from in vivo neuroimaging research, which permits longitudinal tracking of at-risk individuals, indicates that cholinergic neurodegeneration might play an earlier and more pivotal role in these diseases than was previously appreciated. Despite these advances, our understanding of the organization and functions of the BF cholinergic system mostly derives from nonhuman animal research. In this chapter, we begin with a review of the topographical organization of the BF cholinergic system in rodent and nonhuman primate models. We then discuss basic and clinical neuroscience research in humans, which has started to translate and extend the nonhuman animal research using novel noninvasive neuroimaging techniques. We focus on converging evidence indicating that the selective vulnerability of cholinergic neurons in Alzheimer's and Parkinson's diseases is expressed along a rostral-caudal topography in the BF. We close with a discussion of why this topography of vulnerability in the BF may occur and why it is relevant to the clinician.

Chapter 2 - Chronic traumatic encephalopathy and the nucleus basalis of Meynert

Due to the growing number of chronic traumatic encephalopathy (CTE) cases in the military and contact sports, defining the cellular and molecular substrate of this disorder is crucial. Most classic neuropathological investigations describe cortical tau and, to a lesser extent, amyloid lesions, which may underlie the clinical sequela associated with CTE. The application of modern molecular biologic technology to postmortem human brain tissue has made it possible to evaluate the genetic signature of specific neuronal phenotypes at different stages of CTE pathology. Most recently, molecular pathobiology has been used in the field of CTE, with an emphasis on the cholinergic neurons located within the nucleus basalis of Meynert, which develop tau pathology and are associated with cognitive dysfunction similar to that found in Alzheimer's disease (AD). Quantitative findings derived from single-cell transcript investigations provide clues to our understanding of the selective vulnerability of neurons containing AD-like tau pathology at different stages of CTE. Since human tissue-based studies provide a gold standard for the field of CTE, continued molecular pathological studies are needed to reveal novel drug targets for the treatment of this disorder.

Amyloid β redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade

AbstractBackgroundStrong genetic and experimental evidence indicates toxic amyloid β (Aβ) peptides as a key driving factor of Alzheimer’s disease (AD) pathogenesis. The microtubule‐associated protein tau is an essential mediator of Aβ toxicity. Yet, the molecular pathway from Ab to tau pathology remains elusive, presenting a major gap in in‐depth understanding of the pathological cascade of AD. The brain noradrenergic system is highly vulnerable in AD; despite of being a sensitive target of Aβ and tau toxicity, whether it is directly involved in AD pathogenesis is unknown.MethodWe examined the activity of α2A adrenergic receptor (α2AAR) in AD animal models and human postmortem brains using pharmacological methods, performed bioinformatic analysis of cases from the National Alzheimer’s Coordinating Center, characterized Aβ binding of α2AAR using biochemical, cell biological and pharmacological methods, and performed pathological and behavioral studies with AD animal models.ResultIn AD human brains and animal models, α2AAR activity is elevated as compared with non‐AD controls. Activation of this receptor is associated with worsened cognitive function in patients with cognitive deficits. Aβ oligomers bind to an allosteric site on α2AAR with nanomolar affinity. Aβ oligomer binding redirect norepinephrine‐elicited signaling through this receptor to glycogen synthase kinase 3β (GSK3β) activation and tau hyperphosphorylation. This norepinephrine‐dependent mechanism sensitizes pathological GSK3β/tau activation in response to nanomolar accumulations of extracellular Aβ, which is 50‐100 fold lower than the amount required to activate GSK3β by Aβ alone. In vivo treatment with an α2AAR blocker reduces Aβ‐induced GSK3β activation and tau hyperphosphorylation. Moreover, this treatment ameliorates AD‐related pathological changes and improves cognitive function in the two independent AD mouse models.ConclusionWe reveal a previously unappreicated direct role of norepinephrine signaling in connecting Aβ and tau, two key pathological components of AD pathogenesis. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis and longitudinal clinical data. Our study provides translational insights into mechanisms underlying Aβ proteotoxicity, which might have strong implications for the interpretation of Aβ clearance trial results and future drug design, and for understanding the selective vulnerability of noradrenergic neurons in AD.

Age-Related Alterations in Prelimbic Cortical Neuron Arc Expression Vary by Behavioral State and Cortical Layer.

Prefrontal cortical and medial temporal lobe connectivity is critical for higher cognitive functions that decline in older adults. Likewise, these cortical areas are among the first to show anatomical, functional, and biochemical alterations in advanced age. The prelimbic subregion of the prefrontal cortex and the perirhinal cortex of the medial temporal lobe are densely reciprocally connected and well-characterized as undergoing age-related neurobiological changes that correlate with behavioral impairment. Despite this fact, it remains to be determined how changes within these brain regions manifest as alterations in their functional connectivity. In our previous work, we observed an increased probability of age-related dysfunction for perirhinal cortical neurons that projected to the prefrontal cortex in old rats compared to neurons that were not identified as projection neurons. The current study was designed to investigate the extent to which aged prelimbic cortical neurons also had altered patterns of Arc expression during behavior, and if this was more evident in those cells that had long-range projections to the perirhinal cortex. The expression patterns of the immediate-early gene Arc were quantified in behaviorally characterized rats that also received the retrograde tracer cholera toxin B (CTB) in the perirhinal cortex to identify projection neurons to this region. As in our previous work, the current study found that CTB+ cells were more active than those that did not have the tracer. Moreover, there were age-related reductions in prelimbic cortical neuron Arc expression that correlated with a reduced ability of aged rats to multitask. Unlike the perirhinal cortex, however, the age-related reduction in Arc expression was equally likely in CTB+ and CTB− negative cells. Thus, the selective vulnerability of neurons with long-range projections to dysfunction in old age may be a unique feature of the perirhinal cortex. Together, these observations identify a mechanism involving prelimbic-perirhinal cortical circuit disruption in cognitive aging.