Vascular access complications associated with resuscitative endovascular balloon occlusion of the aorta in adult trauma patients: A systematic review and meta-analysis.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is gaining popularity worldwide for managing hypotensive trauma patients. Vascular access complications related to REBOA placement have been reported, with some cases resulting in permanent morbidity. We aim to capitalize on the increase in literature to further describe and estimate the incidence of REBOA-associated vascular access complications in adult trauma patients. METHODS: We searched Medline, EMBASE, Scopus, and CINAHL for studies reporting vascular access complications of REBOA in adult trauma patients from inception to October 14, 2021. Studies reporting data from adult trauma patients who underwent REBOA insertion were eligible. Exclusion criteria included patients 15 years and younger, nontrauma patients, non-REBOA use, non-vascular access complications and patient duplication. Study data was abstracted using the PRISMA checklist and verified independently by three reviewers. Meta-analysis of proportions was performed using a random effects model with Freeman-Turkey double-arcsine transformation. Post hoc meta-regression by year of publication, sheath-size, and geographic region was also performed. The incidence of vascular access complications from REBOA insertion was the primary outcome of interest. Subgroup analysis was performed by degree of bias, sheath size, technique of vascular access, provider specialty, geographical region, and publication year. RESULTS: Twenty-four articles were included in the systematic review and the meta-analysis, for a total of 675 trauma patients who underwent REBOA insertion. The incidence of vascular access complications was 8% (95% confidence interval, 5%-13%). In post hoc meta-regression adjusting for year of publication and geographic region, the use of a smaller (7-Fr) sheath was associated with a decreased incidence of vascular access complications (odds ratio, 0.87; 95% confidence interval, 0.75-0.99; p = 0.046; R 2 = 35%; I 2 = 48%). CONCLUSION: This study provides a benchmark for quality of care in terms of vascular access complications related to REBOA insertion in adult trauma patients. Smaller sheath size may be associated with a decrease in vascular access complications. LEVEL OF EVIDENCE: Systematic Review and Meta-Analysis; Level III.

Cholinergic Reinforcement Signaling Is Impaired by Amyloidosis Prior to Its Synaptic Loss.

Alzheimer's disease (AD) is associated with amyloidosis and dysfunction of the cholinergic system, which is crucial for learning and memory. However, the nature of acetylcholine signaling within regions of cholinergic-dependent plasticity and how it changes with experience is poorly understood, much less the impact of amyloidosis on this signaling. Therefore, we optically measure the release profile of acetylcholine to unexpected, predicted, and predictive events in visual cortex (VC)-a site of known cholinergic-dependent plasticity-in a preclinical mouse model of AD that develops amyloidosis. We find that acetylcholine exhibits reinforcement signaling qualities, reporting behaviorally relevant outcomes and displaying release profiles to predictive and predicted events that change as a consequence of experience. We identify three stages of amyloidosis occurring before the degeneration of cholinergic synapses within VC and observe that cholinergic responses in amyloid-bearing mice become impaired over these stages, diverging progressively from age- and sex-matched littermate controls. In particular, amyloidosis degrades the signaling of unexpected rewards and punishments, and attenuates the experience-dependent (1) increase of cholinergic responses to outcome predictive visual cues, and (2) decrease of cholinergic responses to predicted outcomes. Hyperactive spontaneous acetylcholine release occurring transiently at the onset of impaired cholinergic signaling is also observed, further implicating disrupted cholinergic activity as an early functional biomarker in AD. Our findings suggest that acetylcholine acts as a reinforcement signal that is impaired by amyloidosis before pathologic degeneration of the cholinergic system, providing a deeper understanding of the effects of amyloidosis on acetylcholine signaling and informing future interventions for AD.SIGNIFICANCE STATEMENT The cholinergic system is especially vulnerable to the neurotoxic effects of amyloidosis, a hallmark of Alzheimer's disease (AD). Though amyloid-induced cholinergic synaptic loss is thought in part to account for learning and memory impairments in AD, little is known regarding how amyloid impacts signaling of the cholinergic system before its anatomic degeneration. Optical measurement of acetylcholine (ACh) release in a mouse model of AD that develops amyloidosis reveals that ACh signals reinforcement and outcome prediction that is disrupted by amyloidosis before cholinergic degeneration. These observations have important scientific and clinical implications: they implicate ACh signaling as an early functional biomarker, provide a deeper understanding of the action of acetylcholine, and inform on when and how intervention may best ameliorate cognitive decline in AD.

New advances in endocrine hypertension: from genes to biomarkers.

Hypertension (HT) is a major cardiovascular risk factor that affects 10% to 40% of the general population in an age-dependent manner. Detection of secondary forms of HT is particularly important because it allows the targeted management of the underlying disease. Among hypertensive patients, the prevalence of endocrine HT reaches up to 10%. Adrenal diseases are the most frequent cause of endocrine HT and are associated with excess production of mineralocorticoids (mainly primary aldosteronism), glucocorticoids (Cushing syndrome), and catecholamines (pheochromocytoma). In addition, a few rare diseases directly affecting the action of mineralocorticoids and glucocorticoids in the kidney also lead to endocrine HT. Over the past years, genomic and genetic studies have allowed improving our knowledge on the molecular mechanisms of endocrine HT. Those discoveries have opened new opportunities to transfer knowledge to clinical practice for better diagnosis and specific treatment of affected subjects. In this review, we describe the physiology of adrenal hormone biosynthesis and action, the clinical and biochemical characteristics of different forms of endocrine HT, and their underlying genetic defects. We discuss the impact of these discoveries on diagnosis and management of patients, as well as new perspectives related to the use of new biomarkers for improved patient care.

Visual Cues Predictive of Behaviorally Neutral Outcomes Evoke Persistent but Not Interval Timing Activity in V1, Whereas Aversive Conditioning Suppresses This Activity.

Cue-evoked persistent activity is neural activity that persists beyond stimulation of a sensory cue and has been described in many regions of the brain, including primary sensory areas. Nonetheless, the functional role that persistent activity plays in primary sensory areas is enigmatic. However, one form of persistent activity in a primary sensory area is the representation of time between a visual stimulus and a water reward. This "reward timing activity"-observed within the primary visual cortex-has been implicated in informing the timing of visually cued, reward-seeking actions. Although rewarding outcomes are sufficient to engender interval timing activity within V1, it is unclear to what extent cue-evoked persistent activity exists outside of reward conditioning, and whether temporal relationships to other outcomes (such as behaviorally neutral or aversive outcomes) are able to engender timing activity. Here we describe the existence of cue-evoked persistent activity in mouse V1 following three conditioning strategies: pseudo-conditioning (where unpaired, monocular visual stimuli are repeatedly presented to an animal), neutral conditioning (where monocular visual stimuli are paired with a binocular visual stimulus, at a delay), and aversive conditioning (where monocular visual stimuli are paired with a tail shock, at a delay). We find that these conditioning strategies exhibit persistent activity that takes one of three forms, a sustained increase of activity; a sustained decrease of activity; or a delayed, transient peak of activity, as previously observed following conditioning with delayed reward. However, these conditioning strategies do not result in visually cued interval timing activity, as observed following appetitive conditioning. Moreover, we find that neutral conditioning increases the magnitude of cue-evoked responses whereas aversive conditioning strongly diminished both the response magnitude and the prevalence of cue-evoked persistent activity. These results demonstrate that cue-evoked persistent activity within V1 can exist outside of conditioning visual stimuli with delayed outcomes and that this persistent activity can be uniquely modulated across different conditioning strategies using unconditioned stimuli of varying behavioral relevance. Together, these data extend our understanding of cue-evoked persistent activity within a primary sensory cortical network and its ability to be modulated by salient outcomes.

Reward Timing and Its Expression by Inhibitory Interneurons in the Mouse Primary Visual Cortex.

The primary sensory cortex has historically been studied as a low-level feature detector, but has more recently been implicated in many higher-level cognitive functions. For instance, after an animal learns that a light predicts water at a fixed delay, neurons in the primary visual cortex (V1) can produce "reward timing activity" (i.e., spike modulation of various forms that relate the interval between the visual stimulus and expected reward). Local manipulations to V1 implicate it as a site of learning reward timing activity (as opposed to simply reporting timing information from another region via feedback input). However, the manner by which V1 then produces these representations is unknown. Here, we combine behavior, in vivo electrophysiology, and optogenetics to investigate the characteristics of and circuit mechanisms underlying V1 reward timing in the head-fixed mouse. We find that reward timing activity is present in mouse V1, that inhibitory interneurons participate in reward timing, and that these representations are consistent with a theorized network architecture. Together, these results deepen our understanding of V1 reward timing and the manner by which it is produced.

NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats.

Epidemiological, preclinical, and clinical studies have suggested a role for microdose lithium in reducing Alzheimer's disease (AD) risk by modulating key mechanisms associated with AD pathology. The novel microdose lithium formulation, NP03, has disease-modifying effects in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis at pre-plaque stages, before frank amyloid-ß (Aß) plaque deposition, during which Aß is primarily intraneuronal. Here, we are interested in determining whether the positive effects of microdose lithium extend into early Aß post-plaque stages. We administered NP03 (40µg Li/kg; 1 ml/kg body weight) to McGill-R-Thy1-APP transgenic rats for 12 weeks spanning the transition phase from plaque-free to plaque-bearing. The effect of NP03 on remote working memory was assessed using the novel object recognition task. Levels of human Aß38, Aß40, and Aß42 as well as levels of pro-inflammatory mediators were measured in brain-extracts and plasma using electrochemiluminescent assays. Mature Aß plaques were visualized with a thioflavin-S staining. Vesicular acetylcholine transporter (VAChT) bouton density and levels of chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-6 (IL-6), and 4-hydroxynonenal (4-HNE) were probed using quantitative immunohistochemistry. During the early Aß post-plaque stage, we find that NP03 rescues functional deficits in object recognition, reduces loss of cholinergic boutons in the hippocampus, reduces levels of soluble and insoluble cortical Aß42 and reduces hippocampal Aß plaque number. In addition, NP03 reduces markers of neuroinflammation and cellular oxidative stress. Together these results indicate that microdose lithium NP03 is effective at later stages of amyloid pathology, after appearance of Aß plaques.

Compromise of cortical proNGF maturation causes selective retrograde atrophy in cholinergic nucleus basalis neurons.

The degeneration of basal forebrain cholinergic neurons (BFCNs) in Alzheimer's disease (AD) contributes to cognitive impairment. Nerve growth factor (NGF) secreted in the cerebral cortex is necessary for the phenotypic maintenance of BFCNs. AD is associated with disturbances in NGF metabolism, leading to reduced mature NGF levels and to an accumulation of its precursor, proNGF. We previously described that, in rats, this neurotrophic imbalance is sufficient to induce a loss of cortical cholinergic synapses. In the present study, we investigated whether this neurotrophic imbalance can produce an AD-like retrograde degeneration of BFCNs. Using a combination of retrograde labeling and quantitative cell imaging, we could demonstrate that inhibiting cortical proNGF maturation results in an atrophy of BFCNs, a downregulation of the NGF receptors p75 neurotrophin receptor and tropomyosin receptor kinase A, and a reduction in choline acetyltransferase protein expression. The transient increase in sortilin levels and the sustained colocalization with p75 neurotrophin receptor suggest a participation of proNGF in this degenerative process. This study demonstrates that impairments in the extracellular maturation of proNGF are sufficient to cause a somatodendritic retrograde degeneration of the BFCNs.

Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease.

Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Aß) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of NGF and BDNF transcripts and protein expression. While BDNF mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Paradoxically, the protein levels of the NGF precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimer's disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of NGF were evident in McGill transgenic rats, in line with the paradoxical upregulation of proNGF, as seen in Alzheimer's disease, in the absence of changes in NGF mRNA. The compromise in NGF metabolism and BDNF levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of NGF and BDNF neurotrophins, whereby deficits in BDNF mRNA appear at early stages of intraneuronal Aß pathology, before alterations in NGF metabolism and cholinergic synapse loss manifest.

Intraneuronal Amyloid Beta Accumulation Disrupts Hippocampal CRTC1-Dependent Gene Expression and Cognitive Function in a Rat Model of Alzheimer Disease.

In Alzheimer disease (AD), the accumulation of amyloid beta (Aß) begins decades before cognitive symptoms and progresses from intraneuronal material to extracellular plaques. To date, however, the precise mechanism by which the early buildup of Aß peptides leads to cognitive dysfunction remains unknown. Here, we investigate the impact of the early Aß accumulation on temporal and frontal lobe dysfunction. We compared the performance of McGill-R-Thy1-APP transgenic AD rats with wild-type littermate controls on a visual discrimination task using a touchscreen operant platform. Subsequently, we conducted studies to establish the biochemical and molecular basis for the behavioral alterations. It was found that the presence of intraneuronal Aß caused a severe associative learning deficit in the AD rats. This coincided with reduced nuclear translocation and genomic occupancy of the CREB co-activator, CRTC1, and decreased production of synaptic plasticity-associated transcripts Arc, c-fos, Egr1, and Bdnf. Thus, blockade of CRTC1-dependent gene expression in the early, preplaque phase of AD-like pathology provides a molecular basis for the cognitive deficits that figure so prominently in early AD.

The Multi-Target Drug M30 Shows Pro-Cognitive and Anti-Inflammatory Effects in a Rat Model of Alzheimer's Disease.

Current therapies for Alzheimer's disease (AD) offer partial symptomatic relief and do not modify disease progression. There is substantial evidence indicating a disease onset years before clinical diagnosis, at which point no effective therapy has been found. In this study, we investigated the efficacy of a new multi-target drug, M30, at relatively early stages of the AD-like amyloid pathology in a robust rat transgenic model. McGill-R-Thy1-APP transgenic rats develop the full AD-like amyloid pathology in a progressive fashion, and have a minimal genetic burden. McGill rats were given 5 mg/kg M30 or vehicle per os, every 2 days for 4 months, starting at a stage where the transgenic animals suffer detectable cognitive impairments. At the completion of the treatment, cognitive functions were assessed with Novel Object Location and Novel Object Recognition tests. The brains were then analyzed to assess amyloid-ß (Aß) burden and the levels of key inflammatory markers. Long-term treatment with M30 was associated with both the prevention and the reversal of transgene-related cognitive decline. The effects on cognition were accompanied by a shift of the Aß-immunoreactive material toward an amyloid plaque aggregated molecular form, diminished molecular signs of CNS inflammation and a change in microglia morphology toward a surveying phenotype. This study is the first to demonstrate the therapeutic potential of M30 in a rat model of the AD amyloid pathology. It provides a rationale for further investigations with M30 and with potential multi-target approaches to delay, prevent or reverse the progression the AD pathology at early disease-stages.

Intracellular Aß pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study.

Numerous studies have implicated the abnormal accumulation of intraneuronal amyloid-ß (Aß) as an important contributor to Alzheimer's disease (AD) pathology, capable of triggering neuroinflammation, tau hyperphosphorylation and cognitive deficits. However, the occurrence and pathological relevance of intracellular Aß remain a matter of controversial debate. In this study, we have used a multidimensional approach including high-magnification and super-resolution microscopy, cerebro-spinal fluid (CSF) mass spectrometry analysis and ELISA to investigate the Aß pathology and its associated cognitive impairments, in a novel transgenic rat model overexpressing human APP. Our microscopy studies with quantitative co-localization analysis revealed the presence of intraneuronal Aß in transgenic rats, with an immunological signal that was clearly distinguished from that of the amyloid precursor protein (APP) and its C-terminal fragments (CTFs). The early intraneuronal pathology was accompanied by a significant elevation of soluble Aß42 peptides that paralleled the presence and progression of early cognitive deficits, several months prior to amyloid plaque deposition. Aß38, Aß39, Aß40 and Aß42 peptides were detected in the rat CSF by MALDI-MS analysis even at the plaque-free stages; suggesting that a combination of intracellular and soluble extracellular Aß may be responsible for impairing cognition at early time points. Taken together, our results demonstrate that the intraneuronal development of AD-like amyloid pathology includes a mixture of molecular species (Aß, APP and CTFs) of which a considerable component is Aß; and that the early presence of these species within neurons has deleterious effects in the CNS, even before the development of full-blown AD-like pathology.

Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer's disease.

Chronic brain inflammation is associated with Alzheimer's disease (AD) and is classically attributed to amyloid plaque deposition. However, whether the amyloid pathology can trigger early inflammatory processes before plaque deposition remains a matter of debate. To address the possibility that a pre-plaque inflammatory process occurs, we investigated the status of neuronal, astrocytic, and microglial markers in pre- and post-amyloid plaque stages in a novel transgenic rat model of an AD-like amyloid pathology (McGill-R-Thy1-APP). In this model, we found a marked upregulation of several classical inflammatory markers such as COX-2, IL-1ß, TNF-α, and fractalkine (CX3CL1) in the cerebral cortex and hippocampus. Interestingly, many of these markers were highly expressed in amyloid beta-burdened neurons. Activated astrocytes and microglia were associated with these Aß-burdened neurons. These findings confirm the occurrence of a proinflammatory process preceding amyloid plaque deposition and suggest that Aß-burdened neurons play a crucial role in initiating inflammation in AD.

Inhibition of endogenous NGF degradation induces mechanical allodynia and thermal hyperalgesia in rats.

BACKGROUND: We have previously shown a sprouting of sympathetic fibers into the upper dermis of the skin following subcutaneous injection of complete Freund's adjuvant (CFA) into the hindpaw. This sprouting correlated with an increase in pain-related sensitivity. We hypothesized that this sprouting and pain-related behavior were caused by an increase in nerve growth factor (NGF) levels. In this study, we investigated whether the inhibition of mature NGF degradation, using a matrix metalloproteinase 2 and 9 (MMP-2/9) inhibitor, was sufficient to reproduce a similar phenotype. RESULTS: Behavioral tests performed on male Sprague-Dawley rats at 1, 3, 7 and 14 days after intra-plantar MMP-2/9 inhibitor administration demonstrated that acute and chronic injections of the MMP-2/9 inhibitor induced sensitization, in a dose dependent manner, to mechanical, hot and cold stimuli as measured by von Frey filaments, Hargreaves and acetone tests, respectively. Moreover, the protein levels of mature NGF (mNGF) were increased, whereas the levels and enzymatic activity of matrix metalloproteinase 9 were reduced in the glabrous skin of the hind paw. MMP-2/9 inhibition also led to a robust sprouting of sympathetic fibers into the upper dermis but there were no changes in the density of peptidergic nociceptive afferents. CONCLUSIONS: These findings indicate that localized MMP-2/9 inhibition provokes a pattern of sensitization and fiber sprouting comparable to that previously obtained following CFA injection. Accordingly, the modulation of endogenous NGF levels should be considered as a potential therapeutic target for the management of inflammatory pain associated with arthritis.

Evidence for the accumulation of Abeta immunoreactive material in the human brain and in transgenic animal models.

In this review we highlight the evidence for an intracellular origin of Abeta (Aß) amyloid peptides as well as the observations for a pathological accumulation of these peptides in Alzheimer's disease and Down syndrome, as well as in transgenic animal models. We deliberate on the controversy as to whether the intracellular Aß immunoreactive material is simply an accumulation of unprocessed full length amyloid precursor protein (APP) or a mix of processed APP fragments including Aß. Finally, we discuss the possible pathological significance of these intracellular APP fragments and the expected future research directions regarding this thought-provoking problem.

Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology.

BACKGROUND: A growing body of evidence indicates that inflammation is one of the earliest neuropathological events in Alzheimer's disease. Accordingly, we have recently shown the occurrence of an early, pro-inflammatory reaction in the hippocampus of young, three-month-old transgenic McGill-Thy1-APP mice in the absence of amyloid plaques but associated with intracellular accumulation of amyloid beta petide oligomers. The role of such a pro-inflammatory process in the progression of the pathology remained to be elucidated. METHODS AND RESULTS: To clarify this we administered minocycline, a tetracyclic derivative with anti-inflammatory and neuroprotective properties, to young, pre-plaque McGill-Thy1-APP mice for one month. The treatment ended at the age of three months, when the mice were still devoid of plaques. Minocycline treatment corrected the up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 observed in young transgenic placebo mice. Furthermore, the down-regulation of inflammatory markers correlated with a reduction in amyloid precursor protein levels and amyloid precursor protein-related products. Beta-site amyloid precursor protein cleaving enzyme 1 activity and levels were found to be up-regulated in transgenic placebo mice, while minocycline treatment restored these levels to normality. The anti-inflammatory and beta-secretase 1 effects could be partly explained by the inhibition of the nuclear factor kappa B pathway. CONCLUSIONS: Our study suggests that the pharmacological modulation of neuroinflammation might represent a promising approach for preventing or delaying the development of Alzheimer's disease neuropathology at its initial, pre-clinical stages. The results open new vistas to the interplay between inflammation and amyloid pathology.

Impact of the NGF maturation and degradation pathway on the cortical cholinergic system phenotype.

Cortical cholinergic atrophy plays a significant role in the cognitive loss seen with aging and in Alzheimer's disease (AD), but the mechanisms leading to it remain unresolved. Nerve growth factor (NGF) is the neurotrophin responsible for the phenotypic maintenance of basal forebrain cholinergic neurons in the mature and fully differentiated CNS. In consequence, its implication in cholinergic atrophy has been suspected; however, no mechanistic explanation has been provided. We have previously shown that the precursor of NGF (proNGF) is cleaved extracellularly by plasmin to form mature NGF (mNGF) and that mNGF is degraded by matrix metalloproteinase 9. Using cognitive-behavioral tests, Western blotting, and confocal and electron microscopy, this study demonstrates that a pharmacologically induced chronic failure in extracellular NGF maturation leads to a reduction in mNGF levels, proNGF accumulation, cholinergic degeneration, and cognitive impairment in rats. It also shows that inhibiting NGF degradation increases endogenous levels of the mature neurotrophin and increases the density of cortical cholinergic boutons. Together, the data point to a mechanism explaining cholinergic loss in neurodegenerative conditions such as AD and provide a potential therapeutic target for the protection or restoration of this CNS transmitter system in aging and AD.

Correlation of cognitive performance and morphological changes in neocortical pyramidal neurons in aging.

It is well established that the cerebral cortex undergoes extensive remodeling in aging. In this study, we used behaviorally characterized rats to correlate age-related morphological changes with cognitive impairment. For this, young and aged animals were tested in the Morris water maze to evaluate their cognitive performance. Following behavioral characterization, the animals were perfused and a combination of intracellular labeling and immunohistochemistry was applied. Using this approach, we characterized the dendritic morphology of cortical pyramidal neurons as well as the pattern of glutamatergic and GABAergic appositions on their cell bodies and dendrites. We focused on the association region of the parietal cortex (LtPA) and the medial prefrontal cortex (mPFC) for their involvement in the Morris water maze task. We found an age-related atrophy of distal basal dendrites that did not differ between aged cognitively unimpaired (AU) and aged cognitively impaired animals (AI). Dendritic spines and glutamatergic appositions generally decreased from young to AU and from AU to AI rats. On the other hand, GABAergic appositions only showed a trend towards a decrease in AU rats. Collectively, the data show that the ratio of excitatory/inhibitory inputs was only altered in AI animals. When cortical cholinergic varicosities were labeled on alternate sections, we found that AI animals also had a significant reduction of cortical cholinergic boutons compared with AU or young animals. In aged animals, the density of cortical cholinergic varicosities correlated with the excitatory/inhibitory ratio. Our data suggest that both cholinergic atrophy and an imbalance towards inhibition may contribute to the observed age-associated behavioral impairment.

Changes with aging in the dopaminergic and noradrenergic innervation of rat neocortex.

In normal aging, the mammalian cortex undergoes significant remodeling. Although neuromodulation by dopamine and noradrenaline in the cortex is known to be important for proper cognitive function, little is known on how cortical noradrenergic and dopaminergic presynaptic boutons are affected in normal aging. Using rats we investigated whether these two neurotransmitter systems undergo structural reorganization in aging, and if these changes correlated with cognitive loss. Young and aged rats were tested for cognitive performance using the Morris water maze. Following the behavioral characterization, the animals were sacrificed and the cortical tissue was processed for immunofluorescence using antibodies directed against tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) to detect and discriminate noradrenergic and dopaminergic varicosities. We observed a significant increase in dopaminergic varicosities in lamina V of the anterior cingulate cortex (ACC) of aged cognitively unimpaired rats when compared to young and aged-impaired animals. In laminae II and III of the ACC, we observed a significant decrease of dopaminergic varicosities in aged-impaired animals when compared to young or aged cognitively unimpaired animals. Changes in noradrenergic varicosities never reached statistical significance in any group or brain region. The data suggests that the remodeling of mesocortical dopaminergic fibers may participate in age-associated cognitive decline.

Engagement of the PFC in consolidation and recall of recent spatial memory.

The standard model of system consolidation proposes that memories are initially hippocampus dependent and become hippocampus independent over time. Previous studies have demonstrated the involvement of the medial prefrontal cortex (mPFC) in the retrieval of remote memories. The transformations required to make a memory undergo system's consolidation are thought to require synaptic plasticity. In this study, we investigated the participation of the mitogen-activated protein kinase (MAPK)/ERK pathway in acquisition, memory consolidation, and recent memory recall of the Morris water maze (MWM) task using a 1-d training protocol. To this end, bilateral injections of the MEK inhibitor U0126 into the rat mPFC were performed. The injection of the MEK inhibitor in the mPFC did not affect the acquisition of the MWM. However, MEK inhibitor resulted in impairments on recent memory retrieval either when applied at the end of the learning phase (memory consolidation) or prior to the retention test. The results strongly support the concept that recently acquired and consolidated spatial memories require the mPFC, and that local activation of the MAPK/ERK pathway in the mPFC is necessary for the consolidation and recall of recent memories.