Brain Metabolic Activity Research Articles

IMAGING IN ALZHEIMER'S DISEASE TRIALS: IMPACT ON PATIENT RECRUITMENT, RETENTION AND LOGISTICS

MRI and PET is now extensively utilized in AD trials for patient eligibility, efficacy assessment efficacy, and safety evaluations. Standardization of MRI and PET methodology across the sites is essential to acquire consistent data. This requires prospective site qualification, evaluation of phantom data, training and continuous monitoring. Phantom imaging and standardization is especially important for estimation of brain volumes and PET data. Patient Eligibility: Many neurological diseases like vascular dementia, multiple sclerosis, vascular pathology, neoplasms have similar presentation as AD or could confound the assessment of drug therapy. Inclusion of wrong patients has ethical and legal issues and data could be excluded from the analysis. Eligibility evaluation and optimization of eligibility read process will be discussed. Evaluation of Amyloid Related Imaging Abnormalities (ARIA): ARIA were observed in amyloid-β trials. MRI findings of ARIA include vasogenic edema (ARIA E), micro and macro hemorrhages (ARIA H) and superficial siderosis. FDA had mandated frequent MRIs in all AD trials putting burden on sites and patients. Our experience in ARIA evaluations in large phase III study at >350 sites will be presented. new guidance will also be discussed Efficacy evaluation: MRI is utilized to evaluate various volumes of brain. FDG PET has been used to measure metabolic activity of brain. We will share our experience about site and central independent reads. MRI and PET are used for patient eligibility, efficacy and safety assessments. Imaging must be prospectively planned including standardizing imaging methodologies, site selection process and selecting eligibility and efficacy criteria. Training should be transparently conducted and documented.

Acute and short-term effects of caloric restriction on metabolic profile and brain activation in obese, postmenopausal women.

Early anthropometric and metabolic changes during a caloric-restricted diet in obese postmenopausal women and correlations between these factors with activity in brain areas involved in processing of visual food related stimuli were investigated. An 8-week prospective intervention study of 18 healthy postmenopausal women, with a body mass index of 30-35 kg m-2. The first 2 weeks subjects were on an isocaloric diet and 4 weeks on a 1000 kcal restricted diet followed by 2 weeks on an isocaloric diet. Anthropometric and laboratory analyses were performed weekly during the isocaloric diet and three times a week during the caloric-restricted diet. Functional magnetic resonance imaging scans were obtained before and after the caloric restriction in four separate sessions (fasting or sated). Generalized Estimating Equations analysis was used for data analysis. A mean weight loss of 4.2±0.5 kg (4.8%) and a 4.2±0.4 cm decline in waist circumference were achieved. In the first week of caloric restriction, triglyceride, leptin, resistin and adiponectin levels as well as systolic blood pressure decreased and insulin-like growth factor-binding protein 1 levels increased. During and after weight loss, a significant increase in ghrelin levels was observed. Before weight loss, increased activation of the right amygdala was seen in response to food stimuli, and free fatty acids and glucose correlated with activity in various areas involved in food reward processing. After weight loss, fasting ghrelin and sated leptin levels correlated with activity in these areas. Already in the first week of caloric restriction in obese postmenopausal women, various favourable metabolic changes occur before clinically relevant weight loss is achieved. Activity in the amygdala region and correlations of metabolic factors with activity in brain areas involved in food reward processing differ substantially before and after weight loss.

Event-related changes of the prefrontal cortex oxygen delivery and metabolism during driving measured by hyperspectral fNIRS.

Recent technological advancements in optical spectroscopy allow for the construction of hyperspectral (broadband) portable tissue oximeters. In a series of our recent papers we have shown that hyperspectral NIRS (hNIRS) has similar or better capabilities in the absolute tissue oximetry as frequency-domain NIRS, and that hNIRS is also very efficient in measuring temporal changes in tissue hemoglobin concentration and oxygenation. In this paper, we extend the application of hNIRS to the measurement of event-related hemodynamic and metabolic functional cerebral responses during simulated driving. In order to check if hNIRS can detect event-related changes in the brain, we measured the concentration changes of oxygenated (HbO2) and deoxygenated (HHb) hemoglobin and of the oxidized state of cytochrome c oxidase, on the right and left prefrontal cortices (PFC) simultaneously during simulated driving on sixteen healthy right-handed participants (aged between 22-32). We used our in-house hNIRS system based on a portable spectrometer with cooled CCD detector and a driving simulator with a fully functional steering wheel and foot pedals. Each participant performed different driving tasks and participants were distracted during some driving conditions by asking general knowledge true/false questions. Our findings suggest that more complex driving tasks (non-distracted) deactivate PFC while distractions during driving significantly activate PFC, which is in agreement with previous fMRI results. Also, we found the changes in the redox state of the cytochrome C oxidase to be very consistent with those in the concentrations of HbO2 and HHb. Overall our findings suggest that in addition to the suitability of absolute tissue oximetry, hyperspectral NIRS may also offer advantages in functional brain imaging. In particular, it can be used to measure the metabolic functional brain activity during actual driving.

Central and peripheral pathogenetic forms of type 2 diabetes: a proof-of-concept study.

HypothesisPrevious studies provide evidence that glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) should not be considered as interchangeable alternatives in the diagnosis of the same type 2 diabetes, but as indicators of its different pathogenetic subtypes. This study was conducted to determine whether a particularly high amount of glucose in either HbA1c form or in fasting plasma would be found in diabetic patients genetically predisposed for either intensive cognitive or intensive muscle metabolic activity, respectively.MethodsHbA1c and FPG levels, polymorphisms of genes indicating the predisposition to different cognitive activity (the dopamine D2 receptor (DRD2/ANKK1)), muscle activity (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1A(PPARGC1A))), and vascular regulation of general metabolic activity (the angiotensin 1 converting enzyme (ACE)) were assessed in diabetic patients and nondiabetic controls.ResultsDRD2/ANKK1 polymorphism that affects baseline central arousal determined HbA1c variations uncorrelated with FPG in total and clinical groups. The mutation of PGC1A mainly affecting peripheral glucose metabolism had an effect on FPG correlated or uncorrelated with HbA1c depending on the effect assessment in the total sample or in the nondiabetic group, respectively. ACE insertion/deletion (I/D) gene polymorphism was associated with both HbA1c and FPG fluctuations, but only in diabetic patients.ConclusionThe findings provide evidence that the HbA1c and FPG may predict the risks for different subtypes of type 2 diabetes associated with either brain or muscle metabolic activity in genetically vulnerable people.

Brain imaging and cognition in young narcoleptic patients

The relationship between functional brain images and performances in narcoleptic patients and controls is a new field of investigation.We studied 71 young, type 1 narcoleptic patients and 20 sex- and age-matched control individuals using brain positron emission tomography (PET) images and neurocognitive testing. Clinical investigation was carried out using sleep–wake evaluation questionnaires; a sleep–wake study was conducted with actigraphy, polysomnography, multiple sleep latency test (MSLT), and blood tests (with human leukocyte antigen typing). The continuous performance test (CPT) and Wisconsin card sorting test (WCST) were administered on the same day as the PET study. PET data were analyzed using Statistical Parametric Mapping (version 8) software.Correlation of brain imaging and neurocognitive function was performed by Pearson's correlation. Statistical analyses (Student's t-test) were conducted with SPSS version-18.Seventy-one narcoleptic patients (mean age: 16.15 years, 41 boys (57.7%)) and 20 controls (mean age: 15.1 years, 12 boys (60%)) were studied. Results from the CPT and WCST showed significantly worse scores in narcoleptic patients than in controls (P < 0.05). Compared to controls, narcoleptic patients presented with hypometabolism in the right mid-frontal lobe and angular gyrus (P < 0.05) and significant hypermetabolism in the olfactory lobe, hippocampus, parahippocampus, amygdala, fusiform, left inferior parietal lobe, left superior temporal lobe, striatum, basal ganglia and thalamus, right hypothalamus, and pons (P < 0.05) in the PET study. Changes in brain metabolic activity in narcoleptic patients were positively correlated with results from the sleepiness scales and performance tests.Young, type 1 narcoleptic patients face a continuous cognitive handicap. Our imaging cognitive test protocol can be useful for investigating the effects of treatment trials in these patients.

Insight into the Molecular Imaging of Alzheimer's Disease.

Alzheimer's disease is a complex neurodegenerative disease affecting millions of individuals worldwide. Earlier it was diagnosed only via clinical assessments and confirmed by postmortem brain histopathology. The development of validated biomarkers for Alzheimer's disease has given impetus to improve diagnostics and accelerate the development of new therapies. Functional imaging like positron emission tomography (PET), single photon emission computed tomography (SPECT), functional magnetic resonance imaging (fMRI), and proton magnetic resonance spectroscopy provides a means of detecting and characterising the regional changes in brain blood flow, metabolism, and receptor binding sites that are associated with Alzheimer's disease. Multimodal neuroimaging techniques have indicated changes in brain structure and metabolic activity, and an array of neurochemical variations that are associated with neurodegenerative diseases. Radiotracer-based PET and SPECT potentially provide sensitive, accurate methods for the early detection of disease. This paper presents a review of neuroimaging modalities like PET, SPECT, and selected imaging biomarkers/tracers used for the early diagnosis of AD. Neuroimaging with such biomarkers and tracers could achieve a much higher diagnostic accuracy for AD and related disorders in the future.

MDMA, Methylone, and MDPV: Drug-Induced Brain Hyperthermia and Its Modulation by Activity State and Environment.

Psychomotor stimulants are frequently used by humans to intensify the subjective experience of different types of social interactions. Since psychomotor stimulants enhance metabolism and increase body temperatures, their use under conditions of physiological activation and in warm humid environments could result in pathological hyperthermia, a life-threatening symptom of acute drug intoxication. Here, we will describe the brain hyperthermic effects of MDMA, MDPV, and methylone, three structurally related recreational drugs commonly used by young adults during raves and other forms of social gatherings. After a short introduction on brain temperature and basic mechanisms underlying its physiological fluctuations, we will consider how MDMA, MDPV, and methylone affect brain and body temperatures in awake freely moving rats. Here, we will discuss the role of drug-induced heat production in the brain due to metabolic brain activation and diminished heat dissipation due to peripheral vasoconstriction as two primary contributors to the hyperthermic effects of these drugs. Then, we will consider how the hyperthermic effects of these drugs are modulated under conditions that model human drug use (social interaction and warm ambient temperature). Since social interaction results in brain and body heat production, coupled with skin vasoconstriction that impairs heat loss to the external environment, these physiological changes interact with drug-induced changes in heat production and loss, resulting in distinct changes in the hyperthermic effects of each tested drug. Finally, we present our recent data, in which we compared the efficacy of different pharmacological strategies for reversing MDMA-induced hyperthermia in both the brain and body. Specifically, we demonstrate increased efficacy of the centrally acting atypical neuroleptic compound clozapine over the peripherally acting vasodilator drug, carvedilol. These data could be important for understanding the potential dangers of MDMA in humans and the development of pharmacological tools to alleviate drug-induced hyperthermia - potentially saving the lives of highly intoxicated individuals.

Learning from brain control: clinical application of brain–computer interfaces

Abstract Brain-computer interfaces (BCI) use neuroelectric and metabolic brain activity to activate peripheral devices and computers without mediation of the motor system. In order to activate the BCI patients have to learn a certain amount of brain control. Self-regulation of brain activity was found to follow the principles of skill learning and instrumental conditioning. This review focuses on the clinical application of brain-computer interfaces in paralyzed patients with locked-in syndrome and completely locked-in syndrome (CLIS). It was shown that electroencephalogram (EEG)-based brain-computer interfaces allow selection of letters and words in a computer menu with different types of EEG signals. However, in patients with CLIS without any muscular control, particularly of eye movements, classical EEG-based brain-computer interfaces were not successful. Even after implantation of electrodes in the human brain, CLIS patients were unable to communicate. We developed a theoretical model explaining this fundamental deficit in instrumental learning of brain control and voluntary communication: patients in complete paralysis extinguish goal-directed responseoriented thinking and intentions. Therefore, a reflexive classical conditioning procedure was developed and metabolic brain signals measured with near infrared spectroscopy were used in CLIS patients to answer simple questions with a “yes” or “no”-brain response. The data collected so far are promising and show that for the first time CLIS patients communicate with such a BCI system using metabolic brain signals and simple reflexive learning tasks. Finally, brain machine interfaces and rehabilitation in chronic stroke are described demonstrating in chronic stroke patients without any residual upper limb movement a surprising recovery of motor function on the motor level as well as on the brain level. After extensive combined BCI training with behaviorally oriented physiotherapy, significant improvement in motor function was shown in this previously intractable paralysis. In conclusion, clinical application of brain machine interfaces in well-defined and circumscribed neurological disorders have demonstrated surprisingly positive effects. The application of BCIs to psychiatric and clinical-psychological problems, however, at present did not result in substantial improvement of complex behavioral disorders.

Learning from brain control: clinical application of brain–computer interfaces

Brain–computer interfaces (BCI) use neuroelectric and metabolic brain activity to activate peripheral devices and computers without mediation of the motor system. In order to activate the BCI patients have to learn a certain amount of brain control. Self-regulation of brain activity was found to follow the principles of skill learning and instrumental conditioning. This review focuses on the clinical application of brain–computer interfaces in paralyzed patients with locked-in syndrome and completely locked-in syndrome (CLIS). It was shown that electroencephalogram (EEG)-based brain–computer interfaces allow selection of letters and words in a computer menu with different types of EEG signals. However, in patients with CLIS without any muscular control, particularly of eye movements, classical EEG-based brain–computer interfaces were not successful. Even after implantation of electrodes in the human brain, CLIS patients were unable to communicate. We developed a theoretical model explaining this fundamental deficit in instrumental learning of brain control and voluntary communication: patients in complete paralysis extinguish goal-directed response-oriented thinking and intentions. Therefore, a reflexive classical conditioning procedure was developed and metabolic brain signals measured with near infrared spectroscopy were used in CLIS patients to answer simple questions with a “yes” or “no”-brain response. The data collected so far are promising and show that for the first time CLIS patients communicate with such a BCI system using metabolic brain signals and simple reflexive learning tasks. Finally, brain machine interfaces and rehabilitation in chronic stroke are described demonstrating in chronic stroke patients without any residual upper limb movement a surprising recovery of motor function on the motor level as well as on the brain level. After extensive combined BCI training with behaviorally oriented physiotherapy, significant improvement in motor function was shown in this previously intractable paralysis. In conclusion, clinical application of brain machine interfaces in well-defined and circumscribed neurological disorders have demonstrated surprisingly positive effects. The application of BCIs to psychiatric and clinical–psychological problems, however, at present did not result in substantial improvement of complex behavioral disorders.

FOC1-4BRAIN METABOLISM IN ALCOHOLICS WITH AND WITHOUT KORSAKOFF'S SYNDROME

Korsakoff's syndrome (KS) is characterized by macrostructural brain damage affecting notably the thalamus, mammillary bodies and postero-medial cortex. The pathophysiological mechanisms underlying these brain abnormalities remain unclear. FDG-PET at rest provides information on brain metabolism and synaptic activity. The objective of the present study was to examine metabolism in the whole …

Spatial learning-related changes in metabolic brain activity contribute to the delimitation of the hippocampal pallium in goldfish

Comparative neuroanatomical, developmental and functional evidence suggests that the lateral division of the area dorsalis telencephali (Dl) of the teleost fish is homologous to the hippocampus of tetrapods. Nonetheless, some important aspects of the organization of the hippocampal pallium of teleosts are still under discussion and conflicting hypotheses regarding the extension and demarcation of this region have been proposed. Thus, whereas some authors suggest that the entire Dl region, including its dorsal (Dld) and ventral (Dlv) subdivisions, is homologue to the mammalian hippocampus, others claim that only Dlv should be considered as such. To further elucidate this debate, we investigated the role of Dld and Dlv in one of the most unambiguous functions of the hippocampus, spatial learning. We trained goldfish in a spatial constancy task and mapped the activity of Dld, Dlv, and the medial division of the area dorsalis telencephali (Dm) by means of cytochrome oxidase (CO) histochemistry. The results revealed that training goldfish in the spatial constancy task significantly increased the metabolic activity in Dlv, but not in Dld or Dm, suggesting that only Dlv is critically involved in spatial learning and in this regard comparable to the hippocampus. These data provide additional functional support to the hypotheses that consider Dl as a heterogeneous pallial region and propose that Dlv, but not Dld, might be homologous to the hippocampus.

Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction.

MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results.

Main target of minimal hepatic encephalopathy: Morphophysiological, inflammatory and metabolic view

Although often not considered clinically relevant and, therefore, not diagnosed or treated, minimal hepatic encephalopathy (MHE) has been shown to affect daily functioning, quality of life, driving and overall mortality. To discover early impairments involved in MHE, we studied one of its precipitating factors, portal hypertension. Rats were trained on a stimulus–response task using the Morris water maze. Two groups of animals were used: a SHAM (sham-operated) group (n=13) and a portal hypertension (PH) group (n=13). The triple portal vein ligation method was used to create an animal model of an early developmental phase of HE. Brain metabolic activity was studied with cytochrome c-oxidase histochemistry (C.O.). Neuronal nuclear volume was assessed by nucleator probe; the number of glial fibrillary acidic protein-immunoreactive astrocytes (GFAP-IR) and proinflammatory mediators was measured. The results revealed that the PH group was not able to reach the behavioural criterion, in contrast to the SHAM group. The metabolic brain consumption revealed decreased C.O. activity in the ventral striatum. The PH group showed lower density of GFAP-IR and an increase in the tumour necrotic factor-α (TNF-α). The PH group showed decreased neuronal nuclear volume in the dorsal striatum. On the contrary, increased neuronal nuclear volume was found in the ventral striatum. For the first time, a relationship has been established between inflammation, astrocytic and neural damage, and brain metabolic impairment in a model of MHE. Disruption of the striatum and related structures was highlighted as the main target in early stages of HE. Finally, a simple task was presented to assess the subtle impairments found in the clinic, which could provide fresh insights into the development of new tools for the assessment of MHE.

Overexpression of Corticotropin-releasing Hormone (CRH) in the dorsal amygdala alters anxious temperament and brain metabolic activity

Overexpression of Corticotropin-releasing Hormone (CRH) in the dorsal amygdala alters anxious temperament and brain metabolic activity

Congruency of tumour volume delineated by FET PET and MRSI.

In addition to MR imaging, PET imaging of O-(2-[18F]Fluorethyl)-L-Tyrosine (FET) uptake provides information on brain tumour extent and metabolic activity. Similarly, MRS has been shown to be of value for distinguishing high- from low-grade gliomas. Based on 2D spatially resolved MRSI, an overlap between 18FET uptake and the choline/N-acetyl-aspartate (Cho/NAA) ratio of more than 75 % has been reported.

The brain metabolic activity after resuscitation with liposome-encapsulated hemoglobin in a rat model of hypovolemic shock.

We examined the effect of resuscitation with liposome-encapsulated hemoglobin (LEH) on cerebral bioenergetics in a rat model of 45% hypovolemia. The rats were resuscitated with isovolemic LEH or saline after 15 minutes of shock and followed up to 6 hours. Untreated hypovolemic rats received no fluid. The cerebral uptake of F-18-fluorodeoxyglucose (FDG) was measured by PET, and at 6 hours, the brain was collected for various assays. Hypovolemia decreased cellular adenosine triphosphate (ATP), phosphocreatine, nicotinamide adenine dinucleotide (NAD)/NADH ratio, citrate synthase activity, glucose-6-phosphate, and nerve growth factor (NGF), even when FDG uptake remained unchanged. The FDG uptake was reduced by saline, but not by LEH infusion. The reduced FDG uptake in saline group was associated with a decrease in hexokinase I expression. The LEH infusion effectively restored ATP content, NAD/NADH ratio, and NGF expression, and reduced the hypovolemia-induced accumulation of pyruvate and ubiquitinated proteins; in comparison, saline was significantly less effective. The LEH infusion was associated with low pH and high anion gap, indicating anionic gap acidosis. The results suggest that hypovolemic shock perturbs glucose metabolism at the level of pyruvate utilization, resulting in deranged cerebral energy stores. The correction of volume and oxygen deficits by LEH recovers the cerebral metabolism and creates a prosurvival phenotype.

Mapping human brain capillary water lifetime: high-resolution metabolic neuroimaging.

Shutter‐speed analysis of dynamic‐contrast‐agent (CA)‐enhanced normal, multiple sclerosis (MS), and glioblastoma (GBM) human brain data gives the mean capillary water molecule lifetime (τ b) and blood volume fraction (v b; capillary density–volume product (ρ † V)) in a high‐resolution 1H2O MRI voxel (40 μL) or ROI. The equilibrium water extravasation rate constant, k po (τ b −1), averages 3.2 and 2.9 s−1 in resting‐state normal white matter (NWM) and gray matter (NGM), respectively (n = 6). The results (italicized) lead to three major conclusions. (A) k po differences are dominated by capillary water permeability (P W †), not size, differences. NWM and NGM voxel k po and vb values are independent. Quantitative analyses of concomitant population‐averaged k po, vb variations in normal and normal‐appearing MS brain ROIs confirm PW † dominance. (B) P W † is dominated (>95%) by a trans(endothelial)cellular pathway, not the P CA † paracellular route. In MS lesions and GBM tumors, PCA † increases but PW † decreases. (C) k po tracks steady‐state ATP production/consumption flux per capillary. In normal, MS, and GBM brain, regional k po correlates with literature MRSI ATP (positively) and Na + (negatively) tissue concentrations. This suggests that the PW † pathway is metabolically active. Excellent agreement of the relative NGM/NWM k po vb product ratio with the literature 31PMRSI‐MT CMRoxphos ratio confirms the flux property. We have previously shown that the cellular water molecule efflux rate constant (k io) is proportional to plasma membrane P‐type ATPase turnover, likely due to active trans‐membrane water cycling. With synaptic proximities and synergistic metabolic cooperativities, polar brain endothelial, neuroglial, and neuronal cells form “gliovascular units.” We hypothesize that a chain of water cycling processes transmits brain metabolic activity to k po, letting it report neurogliovascular unit Na+,K+‐ATPase activity. Cerebral k po maps represent metabolic (functional) neuroimages. The NGM 2.9 s−1 k po means an equilibrium unidirectional water efflux of ~1015 H2O molecules s−1 per capillary (in 1 μL tissue): consistent with the known ATP consumption rate and water co‐transporting membrane symporter stoichiometries. © 2015 The Authors NMR in Biomedicine Published by John Wiley & Sons Ltd.

The importance of the context in the hippocampus and brain related areas throughout the performance of a fear conditioning task.

The importance context has been broadly studied in the management of phobias and in the drug addiction literature. The way in which changes to a context influence behavior after the simple acquisition of a passive avoidance task remains unclear. The hippocampus has long been implicated in the contextual and spatial processing required for contextual fear, but its role in encoding the aversive component of a contextual fear memory is still inconclusive. Our work tries to elucidate whether a change in context, represented as differences in the load of the stimuli, is critical for learning about the context-shock association and whether this manipulation of the context could be linked to any change in metabolic brain activity requirements. For this purpose, we used an avoidance conditioning task. Animals were divided into three different experimental conditions. In one group, acquisition was performed in an enriched stimuli environment and retention was performed in a typically lit chamber (the PA-ACQ-CONTX group). In another group, acquisition was performed in the typically lit chamber and retention was undertaken in the highly enriched chamber (the PA-RET-CONTX group). Finally, for the control group, PA-CN-CONTX, acquisition, and retention were performed in the enriched stimuli environment. Our results showed that the PA-ACQ-CONTX group had longer escape latencies and poorer retention than the PA-RET-CONTX and PA-CN-CONTX groups after 24 h of acquisition under contextual changes. To study metabolic brain activity, histochemical labelling of cytochrome c-oxidase (CO) was performed. CO results suggested a neural circuit including the hippocampus, amygdala, thalamus, parahippocampal cortices, and mammillary nuclei that is involved in the learning and memory processes that enable context-dependent behavior. These results highlight how dysfunction in this network may be involved in the contextualization of fear associations that underlie several forms of psychopathology, including post-traumatic stress disorder, schizophrenia, and substance abuse disorders.

Brain functional network changes following Prelimbic area inactivation in a spatial memory extinction task

Several studies suggest a prefrontal cortex involvement during the acquisition and consolidation of spatial memory, suggesting an active modulating role at late stages of acquisition processes. Recently, we have reported that the prelimbic and infralimbic areas of the prefrontal cortex, among other structures, are also specifically involved in the late phases of spatial memory extinction. This study aimed to evaluate whether the inactivation of the prelimbic area of the prefrontal cortex impaired spatial memory extinction. For this purpose, male Wistar rats were implanted bilaterally with cannulae into the prelimbic region of the prefrontal cortex. Animals were trained during 5 consecutive days in a hidden platform task and tested for reference spatial memory immediately after the last training session. One day after completing the training task, bilateral infusion of the GABAA receptor agonist Muscimol was performed before the extinction protocol was carried out. Additionally, cytochrome c oxidase histochemistry was applied to map the metabolic brain activity related to the spatial memory extinction under prelimbic cortex inactivation. Results show that animals acquired the reference memory task in the water maze, and the extinction task was successfully completed without significant impairment. However, analysis of the functional brain networks involved by cytochrome oxidase activity interregional correlations showed changes in brain networks between the group treated with Muscimol as compared to the saline-treated group, supporting the involvement of the mammillary bodies at a the late stage in the memory extinction process.

Tissue hypoxia during ischemic stroke: adaptive clues from hypoxia-tolerant animal models.

The treatment and prevention of hypoxic/ischemic brain injury in stroke patients remain a severe and global medical issue. Numerous clinical studies have resulted in a failure to develop chemical neuroprotection for acute, ischemic stroke. Over 150 estimated clinical trials of ischemic stroke treatments have been done, and more than 200 drugs and combinations of drugs for ischemic and hemorrhagic strokes have been developed. Billions of dollars have been invested for new scientific breakthroughs with only limited success. The revascularization of occluded cerebral arteries such as anti-clot treatments of thrombolysis has proven effective, but it can only be used in a 3-4.5h time frame after the onset of a stroke, and not for every patient. This review is about novel insights on how to resist tissue hypoxia from unconventional animal models. Ability to resist tissue hypoxia is an extraordinary ability that is not common in many laboratory animals such as rat and mouse models. For example, we can learn from a naked mole-rat, Chrysemys picta, how to actively regulate brain metabolic activity to defend the brain against fluctuating oxygen tension and acute bouts of oxidative stress following the onset of a stroke. Additionally, a euthermic arctic ground squirrel can teach us how the brain of a stroke patient can remain well oxygenated during tissue hypoxia with no evidence of cellular stress. In this review, we discuss how these animals provide us with a system to gain insight into the possible mechanisms of tissue hypoxia/ischemia. This issue is of clinical significance to stroke patients. We describe specific physiological and molecular adaptations employed by different animals' models of hypoxia tolerance in aquatic and terrestrial environments. We highlight how these adaptations might provide potential clues on strategies to adapt for the clinical management of tissue hypoxia during conditions such as stroke where oxygen demand fails to match the supply.