Normal Cognitive Processes Research Articles

Features and timing of the response of single neurons to novelty in the substantia nigra

Substantia nigra neurons are known to play a key role in normal cognitive processes and disease states. While animal models and neuroimaging studies link dopamine neurons to novelty detection, this has not been demonstrated electrophysiologically in humans. We used single neuron extracellular recordings in awake human subjects undergoing surgery for Parkinson disease to characterize the features and timing of this response in the substantia nigra. We recorded 49 neurons in the substantia nigra. Using an auditory oddball task, we showed that they fired more rapidly following novel sounds than repetitive tones. The response was biphasic with peaks at approximately 250ms, comparable to that described in primate studies, and a second peak at 500ms. This response was primarily driven by slower firing neurons as firing rate was inversely correlated to novelty response. Our data provide human validation of the purported role of dopamine neurons in novelty detection and suggest modifications to proposed models of novelty detection circuitry.

Central auditory functions in elderly individuals

AbstractElderly individuals often have more difficulty in understanding speech than younger adults, particularly in noisy environments. Three models that attempt to explain this are as follows: (a) deterioration in peripheral hearing; (b) structural changes to the central auditory system; and (c) changes in normal cognitive processes. The aim of this study was to assess the central auditory functions in an elderly population and compare them with those of an adult population. Participants and methods The study group included 60 elderly individuals; they were older than 60 years of age and were divided into two subgroups: the first subgroup A included 24 elderly individuals with normal peripheral hearing and the second subgroup B included 36 elderly individuals with presbycusis with a mild degree of hearing loss. The control group included 30 individuals ranging in age from 18 to 30 years. Both the study and the control group were subjected to an otological examination, immittancemetry, pure tone audiometry, speech audiometry, and central auditory processing assessment using the following selected few behavioral central auditory tests: synthetic sentence identification test with ipsilateral competing message (SSI-ICM), dichotic digits test (DDT), auditory fusion test-revised (AFT-R), and pitch pattern sequences test (PPT). Results There were elevated hearing thresholds at mostly all frequencies with statistically significant differences on comparing both study subgroups A and B with the control group. On using SSI-ICM, in the competition ratio (−15 dB), there were statistically significantly low scores in subgroups A and B compared with the control group. Results of DDT showed statistically significantly low scores on comparing the results between the left ear and the right ear in both subgroups A and B. There was a statistically significant elevated gap threshold for tonal stimuli in the AFT-R test on comparing both subgroups A and B with the control group. The results of PPT showed that subgroup B obtained a statistically significantly lower score compared with the control group. There was a statistically significant negative correlation between age and the results of SSI-ICM in the competition ratio 0 dB when presented to the left ear, DDT, and PPT. There was a statistically significant positive correlation between age and the results of AFT-R when presented at 4000 Hz. Conclusion Age-related changes to auditory processing will occur in most adults 60 years of age and older that may or may not be concomitant with peripheral hearing loss. Aging decreases the capacity of digit recognition and also increases interaural asymmetries. Many older listeners show reduced temporal resolution even when potential influences of hearing loss are absent. Temporal ordering abilities decrease with age. Recommendation It is important to include central auditory tests in the audiologic assessment protocol of the elderly. The utilization of these tests in assessment of the elderly enables us to improve the quality of therapeutic-rehabilitative interventions.

Measuring outcome after severe TBI

Objectives: To review current scales for measuring outcome following traumatic brain injury (TBI) and discuss changes in the types and use of these scales for the purposes of facilitating comparative effectiveness research. Methods: Functional, psychosocial/neurocognitive, and quality of life (QOL) scales used for assessing outcome following TBI are presented, along with the limitations of each. Core common data element scales are noted, and parametric, preference-based scales for performing comparative effectiveness research are discussed. Results: Many of the common outcome scales used in TBI research, including the Glasgow outcome scale (GOS), are functional measures. The emotional, cognitive, and psychosocial aspects of recovery are increasingly recognised, and metrics assessing these domains are becoming more common. Quality of life scales, which can be either directly used or translated into parametric preference-based indices for comparative effectiveness research are important for assessing patient-oriented outcomes, and in the upcoming years may yield information that improves medical decision-making, and ultimately outcomes following TBI. Discussion: Traumatic brain injury disrupts normal physical, cognitive, emotional, and social processes. Despite the dominance of functional scales like the GOS in the neurosurgical and neurocritical care literature, the use of other outcome modalities, including emotional, cognitive, psychosocial, and health-related QOL domains will be essential to improve patient care in the future.

Nature or Nurture? Determining the Heritability of Human Striatal Dopamine Function: an [18F]-DOPA PET Study

Striatal dopamine function is important for normal personality, cognitive processes and behavior, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins. Nine MZ and 10 DZ twin pairs underwent high-resolution [18F]-DOPA PET to assess presynaptic striatal dopamine function. Uptake values for the overall striatum and functional striatal subdivisions were determined by a Patlak analysis using a cerebellar reference region. Heritability, shared environmental effects and non-shared individual-specific effects were estimated using a region of interest (ROI) analysis and a confirmatory parametric analysis. Overall striatal heritability estimates from the ROI and parametric analyses were 0.44 and 0.33, respectively. We found a distinction between striatal heritability in the functional subdivisions, with the greatest heritability estimates occurring in the sensorimotor striatum and the greatest effect of individual-specific environmental factors in the limbic striatum. Our results indicate that variation in overall presynaptic striatal dopamine function is determined by a combination of genetic factors and individual-specific environmental factors, with familial environmental effects having no effect. These findings underline the importance of individual-specific environmental factors for striatal dopaminergic function, particularly in the limbic striatum, with implications for understanding neuropsychiatric disorders such as schizophrenia and addictions.

Nerve injury causes long-term attentional deficits in rats

Human chronic pain sufferers frequently report problems with attention and concentration that affect daily functioning and quality of life. Chronic pain is also commonly associated with anxiety and depression. It is currently not known if the pain causes these co-morbidities, or if they are pre-disposing risk factors for the development of chronic pain. Animal studies suggest a possible causative effect of pain on cognition, but usually tests are conducted during acute ongoing pain when the pain may act as a distracter to normal cognitive and emotional processing. Here we examine long-term effects of nerve injury on cognitive functioning in a rat model, which contributes to better understanding of the relationship between cognitive impairment and chronic pain experience in human populations. This study investigated attentional capability, anxiety-like behavior and sensory functioning 6months after spared nerve injury (SNI) surgery—a time-point well beyond the acute pain phase and akin to decades of pain experience in humans. Male Long Evans rats subjected to nerve injury remained hypersensitive to sensory stimuli from the time of injury to the 6-month post-injury assessment. At 6months they were impaired on a visual non-selective, non-sustained attention task and displayed anxiety-like behaviors in the elevated plus maze. These findings show that cognitive disturbances observed during acute pain persist for months in a rodent chronic pain model and suggest that cognitive alterations in chronic pain patients are at least partially caused by the chronic pain state.

The Effect of Chronic Cannabinoids on Broadband EEG Neural Oscillations in Humans

Animal and cellular work has shown that central cannabinoid-1 receptors modulate neural oscillations in the gamma range (40 Hz), which may be important for normal perceptual and cognitive processes. In order to assess the effect of cannabinoids on broadband-frequency neural oscillations in humans, the current study examined the effect of chronic cannabis use on auditory steady-state responses (ASSRs) utilizing electroencephalography (EEG). Passive ASSRs were assessed using varying rates of binaural stimulation (auditory click-trains; 10-50 Hz in increments of 5 Hz; 80 dB SPL) in carefully screened cannabis users and controls. Chronic cannabis users (n=22; 12 h abstinence before study; positive 11-nor-9-carboxy-delta-9-tetrahydrocannabinol urine levels) and cannabis naïve controls (n=24) were evaluated. Time X frequency analyses on EEG data were performed using Fourier-based mean trial power (MTP) and phase-locking (inter-trial coherence; ITC). Transient ERPs to stimulus onset (auditory N100 components) were also evaluated. As predicted, a decrease in spectral power (MTP) at 40 Hz was observed in the cannabis group (p<0.018). No effects on phase-locking (ITC) or the N100 were observed. Further, within the cannabis group, lower 40 Hz power correlated with an earlier age of onset of cannabis use (p<0.04). These data suggest that chronic exposure to exogenous cannabinoids can alter the ability to generate neural oscillations, particularly in the gamma range. This is consistent with preclinical animal and cellular data, which may have implications for understanding the short- and long-term psychopharmacological effects of cannabis.

Computerized video analysis of social interactions in mice

The study of social interactions in mice is used as a model for normal and pathological cognitive and emotional processes. But extracting comprehensive behavioral information from videos of interacting mice is still a challenge. We describe a computerized method and software, MiceProfiler, that uses geometrical primitives to model and track two mice without requiring any specific tagging. The program monitors a comprehensive repertoire of behavioral states and their temporal evolution, allowing the identification of key elements that trigger social contact. Using MiceProfiler we studied the role of neuronal nicotinic receptors in the establishment of social interactions and risk-prone postures. We found that the duration and type of social interactions with a conspecific evolves differently over time in mice lacking neuronal nicotinic receptors (Chrnb2-/-, here called β2(-/-)), compared to C57BL/6J mice, and identified a new type of coordinated posture, called back-to-back posture, that we rarely observed in β2(-/-) mice.

Attentional bias in post-traumatic stress disorder diminishes after symptom amelioration

Background Avoidance and hypervigilance to reminders of a traumatic event are among the main characteristics of post-traumatic stress disorder (PTSD). Attentional bias toward aversive cues in PTSD has been hypothesized as being part of the dysfunction causing etiology and maintenance of PTSD. The aim of the present study was to investigate the cognitive strategy underlying attentional bias in PTSD and whether normal cognitive processing is restored after a treatment suppressing core PTSD symptoms. Methods Nineteen healthy controls were matched for age, sex and education to 19 PTSD patients. We used the emotional stroop and detection of target tasks, before and after an average of 4.1 sessions of eye movement desensitization and reprocessing (EMDR) therapy. Results We found that on both tasks, patients were slower than controls in responding in the presence of emotionally negative words compared to neutral ones. After symptoms removal, patients no longer had attentional bias, and responded similarly to controls. Conclusion These results support the existence of an attentional bias in PTSD patients due to a disengagement difficulty. There was also preliminary evidence that the disengagement was linked to PTSD symptomatology. It should be further explored whether attentional bias and PTSD involve common brain mechanisms.

Epigenetics in the mature mammalian brain: Effects on behavior and synaptic transmission

The role of epigenetic mechanisms in control of gene expression during mammalian development is well established. Associations between specific DNA or histone modifications and numerous neurodevelopmental and neurodegenerative disorders implies significant consequences of epigenetic dysregulation in both the developing and mature brain, the latter of which is the general focus of this review. Accumulating evidence suggests that epigenetic changes are involved in normal cognitive processes in addition to neurological and psychiatric disorders. Recent investigations into the regulation of epigenetic modifications in the adult brain have revealed novel and surprisingly dynamic mechanisms for controlling learning and memory-related behaviors as well as long-term synaptic plasticity. DNA methylation and histone acetylation have also been implicated in the modulation of basal synaptic transmission and the balance between excitation and inhibition in various brain regions. Studies have begun to uncover some of the alterations in gene expression that appear to mediate many of these effects, but an understanding of the precise mechanisms involved is still lacking. Nevertheless, the fundamental importance of epigenetic processes in influencing neuronal activity is becoming increasingly evident.

Evaluating the Role of Serotonin on Neuropsychological Function After Breast Cancer Using Acute Tryptophan Depletion

Although cognitive dysfunction is a prevalent and disruptive problem for many breast cancer survivors (BCSs), little research has examined its etiology. One potential mechanism that remains to be explored is serotonin. Serotonin has been implicated in normal and dysfunctional cognitive processes, and serotonin levels are significantly affected by estrogen withdrawal, a common side effect of breast cancer treatment. However, no study has evaluated serotonin's role on cognitive dysfunction in BCSs. The purpose of this study was to examine the role of serotonin in cognitive dysfunction in survivors by lowering central serotonin concentrations via acute tryptophan depletion (ATD). Based on previous research in noncancer populations, we hypothesized that alterations in central serotonin levels would induce cognitive dysfunction in these women controlling for confounding characteristics such as fluctuating mood and glucose levels. Secondarily, we explored whether genetic variations in serotonin genes would partly explain ATD. Participants included 20 female BCSs, posttreatment for nonmetastatic breast cancer, who received ATD or control in a double-blind, crossover design. Cognitive performance was measured at the 5-hr tryptophan/serotonin nadir on each test day using standardized neuropsychological tests. Specific impairment was noted in episodic memory (delayed recall) and motor speed during ATD versus control. ATD did not alter new learning (immediate recall), working memory, verbal fluency, or information processing speed. Findings suggest that serotonin may play a critical role in memory consolidation and motor functioning in BCSs.

Rapid increase of Nurr1 mRNA expression in limbic and cortical brain structures related to coping with depression‐like behavior in mice

The immediate-early gene Nurr1 is a member of the inducible orphan nuclear receptor family. Nurr1 is essential to the differentiation, maturation, and maintenance of midbrain dopaminergic neurons and is expressed in different brain regions. We have reported that adult mice with reduced Nurr1 expression displayed an increase in immobility response to acute stress. These mice were also deficient in the retention of emotional memory. Thus, Nurr1 expression seems to be relevant to normal cognitive processes. To investigate the response of Nurr1 to a stress stimulus, Nurr1 mRNA expression was examined by in situ hybridization in adult mice using a depression-like behavior paradigm, the forced swim test. The Nurr1 gene was rapidly and widely up-regulated throughout the brain, including cortical areas (i.e., prefrontal cortex, primary and secondary visual cortex, primary auditory cortex, and secondary somatosensory cortex), hippocampus (dentate gyrus, CA1, CA2, and CA3), and midbrain (substantia nigra pars compacta and ventral tegmental area) at 30 min and 3 hr after the forced swim test. Dopamine content was reduced in prefrontal cortex and midbrain following swim stress. These results suggest that the increase in Nurr1 expression might be a compensatory mechanism to counteract the changes in forebrain dopamine transmission in coping with acute stress.

Chronic Opioid Therapy and Preventive Services in Rural Primary Care: An Oregon Rural Practice-based Research Network Study

For clinicians, using opioid therapy for chronic noncancer pain (CNCP) often gives rise to a conflict between treating their patients' pain and fears of addiction, diversion of medication, or legal action. Consequent stresses on clinical encounters might adversely affect some elements of clinical care. We evaluated a possible association between chronic opioid therapy (COT) for CNCP and receipt of various preventive services. We conducted a retrospective cohort study in 7 primary care clinics within the Oregon Rural Practice-based Research Network (ORPRN). Using medical records of 704 patients, aged 35 to 85 years, seen during a 3-year period, we compared the receipt of 4 preventive services between patients on COT for CNCP and patients not on chronic opioid therapy (non-COT). We used multivariate log-binomial regression analyses to estimate the relative risk of receipt of each preventive service. After adjustment for plausible confounders, we found that patients using COT had a statistically significantly lower relative risk (RR) of receipt of cervical cancer screening (RR = 0.60; 95% confidence interval [CI], 0.47-0.76) and colorectal cancer screening (RR = 0.42; 95% CI, 0.22-0.80) when compared with non-COT patients. The RR was reduced, without statistical significance, for lipid screening (RR = 0.77; 95% CI, 0.54-1.10), and not notably reduced for smoking cessation counseling (RR = 0.95; 95% CI, 0.78-1.15). Patients using COT for CNCP were less likely to receive some preventive services. Research is needed to better understand barriers to and improved methods for providing preventive services for these patients.

Gamma oscillations and schizophrenia

In the last 2 decades, it has become apparent that brain regions communicate by coordinating the firing of populations of neurons. When neurons synchronize their firing, their rhythmic input is reflected in the extracellular field potential as brain oscillations. Rhythmic brain activity in animals and humans can be recorded using noninvasive techniques such as electroencephalography (EEG) by placing recording electrodes on the surface of the scalp and, more rarely, intracranially at the surface of a brain region, such as the temporal lobe or hippocampus. Human EEG was developed as early as the 1920s by German psychiatrist Hans Berger and has been in constant use since then. However, in the last 25 years, advances in signal processing and methods for the analysis of EEG spectra have intensified interest in the use of quantitative EEG for research purposes. Additionally, more recently developed magnetoencephalographic (MEG) techniques have shown great potential for measuring weak magnetic fields generated by rhythmic currents in the brain. With these methods, rhythmic activity of various frequencies such as delta (0–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–30 Hz) and gamma (30–200 Hz) can be detected. These neural oscillations are correlated with and are believed to play a role in normal cognitive processes including memory, attention, perceptual binding and consciousness.1

Is the impostor hypothesis really so preposterous? Understanding the Capgras experience

In his classic paper, “Delusional thinking and perceptual disorder,” Brendan Maher (1974) argues that psychiatric delusions are hypotheses designed to explain anomalous experiences, and are “developed through the operation of normal cognitive processes.” Consider, for instance, the Capgras delusion. Patients suffering from this particular delusion believe that someone close to them—such as a spouse, a sibling, a parent, or a child—has been replaced by an impostor: by someone who bears a striking resemblance to the “original” and who (for reasons unknown) is intent on passing herself off as that individual. On Maher's view, the “Impostor Hypothesis” is the response of a rational agent to the anomalous experience it is invoked to explain. Recently, a number of philosophers have argued that Maher's analysis of delusion doesn’t work when applied to the Capgras delusion. In this paper, I defend Maher's analysis against these arguments. However, my aim is not merely to defend Maher's analysis, but also to draw attention to some of the methodological problems that have led to its hasty dismissal.

Alpha7 neuronal nicotinic receptors: The missing link to understanding Alzheimer’s etiopathology?

Evidence supports the premise that alpha7 nicotinic acetylcholine receptors in the central nervous system, sometimes referred to as neuronal nicotinic receptors (NNRs), play a central role in the development of Alzheimer's disease (AD) pathophysiology. Moreover, these receptors may represent the key to unifying aspects of the cholinergic hypothesis of AD with many of the apparently disparate mechanisms such as beta-amyloid deposition, tau hyperphosphorylation, and ApoE4 abnormalities variously proposed to underlie the progression of the disease. We hypothesize that neuronal degeneration in incipient AD is the result of coincident events involving, at their core, deficits in alpha7 NNR function. The resulting hypocholinergic tone could potentially have serious consequences since alpha7 NNRs are known to modulate fundamental pathways involved in cell survival such as JAK2-STAT3. This hypothesis predicts that any factors that compromise alpha7 function have the potential to negatively impact neuronal viability. For example, such factors could include deficits in the primary neurotransmitter acetylcholine (ACh), underactivity of normal cognitive processes that stimulate alpha7 NNRs (i.e., use-dependency), or the reported binding of beta-amyloid and ApoE4 to alpha7 NNRs, all of which could effectively decouple the receptors from key pro-survival pathways. Since these pathways are known to negatively modulate GSK-3beta, which regulates tau phosphorylation, downstream effects such as tau hyperphosphorylation would be expected to arise. Conversely, the maintenance of normal alpha7 NNR activity by adequate levels of ACh or other NNR agonists would be expected to support normal cholinergic tone, prevent the binding of beta-amyloid and ApoE4 and preserve the integrity of the neurons. We therefore propose that decreased cholinergic tone is at the apex of AD pathophysiology, with factors such as beta-amyloid and ApoE4 playing a contributory role rather that a causal one and hyperphosphorylation of tau representing a detector of concomitant hypocholinergic tone and beta-amyloid deposition. Thus the convergence of beta-amyloid deposition and/or ApoE4 binding and co-localization with alpha7 NNRs, which are favored under conditions of low cholinergic tone, and the downstream cascade of tau hyperphosphorylation through disinhibition of GSK-3beta appear to explain and reconcile many of the discordant findings in this very active area of CNS research.

The brain angiotensin IV/AT4 receptor system as a new target for the treatment of Alzheimer's disease

AbstractThe brain renin‐angiotensin system (RAS) regulates several physiologies including blood pressure, body sodium and water balance, cyclicity of reproductive hormones and related sexual behaviors, and the release of pituitary gland hormones. These physiologies are under the control of the angiotensin II (AngII)/AT1 receptor subtype system. The AngII/AT2 receptor subtype system is expressed during fetal development and is less abundant in the adult. This system appears to oppose growth responses facilitated by activation of the AT1 receptor. There is a growing list of nontraditional physiologies mediated by the most recently discovered angiotensin IV (AngIV)/AT4 receptor subtype system that include the regulation of blood flow, modulation of exploratory behaviors, involvement in stress responses and seizure, and a role in learning and memory acquisition. There is evidence to support an inhibitory influence by AngII, and a facilitory role by AngIV, on neuronal firing rate, long‐term potentiation, and associative and spatial learning and memory. These findings suggest an important role for the RAS, and the AT4 receptor in particular, in normal cognitive processing and provide the stimulus for developing drugs that penetrate the blood‐brain barrier to interact with this brain receptor in the treatment of dysfunctional memory. Drug Dev Res 70: 472–480, 2009. © 2009 Wiley‐Liss, Inc.

Dopamine D4Receptors Regulate AMPA Receptor Trafficking and Glutamatergic Transmission in GABAergic Interneurons of Prefrontal Cortex

GABAergic interneurons in prefrontal cortex (PFC) play a critical role in cortical circuits by providing feedforward and feedback inhibition and synchronizing neuronal activity. Impairments in GABAergic inhibition to PFC pyramidal neurons have been implicated in the abnormal neural synchrony and working memory disturbances in schizophrenia. The dopamine D(4) receptor, which is strongly linked to neuropsychiatric disorders, such as attention deficit-hyperactivity disorder (ADHD) and schizophrenia, is highly expressed in PFC GABAergic interneurons, while the physiological role of D(4) in these interneurons is largely unknown. In this study, we found that D(4) activation caused a persistent suppression of AMPAR-mediated synaptic transmission in PFC interneurons. This effect of D(4) receptors on AMPAR-EPSC was via a mechanism dependent on actin/myosin V motor-based transport of AMPA receptors, which was regulated by cofilin, a major actin depolymerizing factor. Moreover, we demonstrated that the major cofilin-specific phosphatase Slingshot, which was activated by calcineurin downstream of D(4) signaling, was required for the D(4) regulation of glutamatergic transmission. Thus, D(4) receptors, by using the unique calcineurin/Slingshot/cofilin signaling mechanism, regulate actin dynamics and AMPAR trafficking in PFC GABAergic interneurons. It provides a potential mechanism for D(4) receptors to control the excitatory synaptic strength in local-circuit neurons and GABAergic inhibition in the PFC network, which may underlie the role of D(4) receptors in normal cognitive processes and mental disorders.

Pharmacotherapeutic targets in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which is characterized by an increasing impairment in normal memory and cognitive processes that significantly diminishes a person's daily functioning. Despite decades of research and advances in our understanding of disease aetiology and pathogenesis, there are still no effective disease-modifying drugs available for the treatment of AD. However, numerous compounds are currently undergoing pre-clinical and clinical evaluations. These candidate pharma-cotherapeutics are aimed at various aspects of the disease, such as the microtubule-associated τ-protein, the amyloid-β (Aβ) peptide and metal ion dyshomeostasis – all of which are involved in the development and progression of AD. We will review the way these pharmacological strategies target the biochemical and clinical features of the disease and the investigational drugs for each category.

Discuss the contribution of cognitive neuropsychology to understanding normal cognitive processes

Discuss the contribution of cognitive neuropsychology to understanding normal cognitive processes

Transthyretin: A key gene involved in the maintenance of memory capacities during aging

Aging is often associated with decline of memory function. Aged animals, like humans, can naturally develop memory impairments and thus represent a useful model to investigate genes involved in long-term memory formation that are differentially expressed between aged memory-impaired (AI) and aged memory-unimpaired (AU) animals following stimulation in a spatial memory task. We found that alterations in hippocampal gene expression of transthyretin (TTR), calcineurin, and NAD(P)H dehydrogenase quinone 2 (NQO2) were associated with memory deficits in aged animals. Decreased TTR gene expression could be attributed at least partially to diminish activity of C/EBP immediate-early gene cascade initiated by CREB since protein levels of C/EBP, a transcription factor regulating both TTR and NQO2 expression, was decreased in AI animals. Memory deficits were also found during aging in mice lacking TTR, a retinol transporter known to prevent amyloid-β aggregation and plaque formation as seen in Alzheimer's disease. Treatment with retinoic acid reversed cognitive deficits in these knock-out mice as well as in aged rats. Our study provides genetic, behavioural and molecular evidence that TTR is involved in the maintenance of normal cognitive processes during aging by acting on the retinoid signalling pathway.