Alterations In Neural Circuits Research Articles

Altered neural inhibition responses to food cues after Roux-en-Y Gastric Bypass

BackgroundRoux-en-Y gastric bypass (RYGB) surgery is a highly effective weight-loss intervention that often reduces preference and intake of high-energy foods. Research into the neural mechanisms behind this shift has mainly focused on reward processing of food cues. However, the ability to successfully control food intake and thereby weight-loss also depends on inhibitory control capacity. We investigated whether RYGB leads to alterations in neural inhibitory control in response to food cues. MethodsA food-specific go/no-go task with pictures of high-energy (desserts) and low-energy foods (vegetables), was used to assess neural inhibition responses before and after RYGB with functional magnetic resonance imaging. Data from 18 morbidly obese patients (15 females; age 41 ± 11 years; BMI 42 ± 4 kg/m2 before; BMI 36 ± 4 kg/m2 after) were analysed. Pre- and post-RYGB BOLD fMRI responses were compared for response inhibition towards high- and low-energy foods. Participants were tested in a satiated state. ResultsResponse inhibition to high-energy foods was associated with increased activation of the right lateral prefrontal cortex (PFC), right medial PFC, dorsolateral PFC, right middle cingulate cortex and the right inferior frontal operculum (involved in inhibitory control), after compared to before surgery. Response inhibition to low-energy foods elicited diminished post- compared to pre-surgery responses in the left superior temporal pole, right parahippocampal gyrus and right hypothalamus (involved in metabolic control). ConclusionNeural changes indicate improved response inhibition towards high-energy food cues, altered influence of metabolic control during response inhibition towards low-energy food cues and a more positive attitude to both high-energy and low-energy food after RYGB. Alterations in neural circuits involved in inhibitory control, satiety signalling and reward processing may contribute to effective weight-loss after RYGB.

18.4 CHARACTERIZING LARGE-SCALE NETWORK DYSCONNECTIVITY IN SCHIZOPHRENIA: MODELING ALTERED E/I BALANCE

BackgroundNeuropsychiatric disorders alter the structure and function of neural circuits and distributed neural networks, which leads to profound behavioral disability such as working memory impairment. Non-invasive neuroimaging tools have matured to reliably detect neural systems-level disturbances in neuropsychiatric disorders. However, mechanistic mapping from neural circuit pathology to abnormal behavior remains out of reach for most psychiatric conditions. We focus on the emerging field of ‘computational psychiatry’ to close these gaps from the perspective of E/I imbalance in schizophrenia with an emphasis on understanding large-Scale network dysconnectivity in schizophrenia.MethodsFirst, we apply computational microcircuit models to understand cognitive and neural system-level disturbances in schizophrenia as a function of altered E/I balance. In turn, the focus is placed on pharmacological neuroimaging as a powerful causal tool to probe neural circuit perturbations. Specific recent neuroimaging studies are discussed that use the NMDA receptor antagonist, ketamine, to probe glutamate synaptic dysfunction associated with schizophrenia. We leverage resting-state neuroimaging advances to inform biomarker development for network alterations in schizophrenia given its ease of data collection and lack of task-based confounds.ResultsPharmacological and clinical results implicate alterations in cortico-striato-thalamic circuits, which might constitute a final common pathway of neural system disturbances in schizophrenia. Results indicate that this functional marker appears in at-risk states, chronic patients, and following pharmacological manipulations following ketamine. Computational simulations implicate altered E/I balance in cortical microcircuits as a parsimonious upstream mechanism.DiscussionThe combined use of biophysical computational modeling, extended to large-scale neural system simulations, has proven particularly powerful to draw inferences about neural circuit alterations that may be ‘driving’ the resting-state dysconnectivity and cognitive deficits in schizophrenia. In summary, present data illustrates a framework for linking experimental studies in humans with computational models and pharmacological probes will advance to effort to bridge cellular, systems, and clinical neuroscience approaches to psychiatric disorders.

A Link Between Childhood Adversity and Trait Anger Reflects Relative Activity of the Amygdala and Dorsolateral Prefrontal Cortex

BackgroundTrait anger, or the dispositional tendency to experience a wide range of situations as annoying or frustrating, is associated with negative mental and physical health outcomes. The experience of adversity during childhood is one risk factor for the later emergence of high trait anger. This association has been hypothesized to reflect alterations in neural circuits supporting bottom-up threat processing and top-down executive control. MethodsHere, using functional magnetic resonance imaging and self-report questionnaire data from 220 volunteers, we examined how individual differences in top-down prefrontal executive control and bottom-up amygdala threat activity modulate the association between childhood adversity and trait anger during young adulthood. ResultsWe report that the association between childhood adversity and trait anger is attenuated specifically in young adults who have both relatively low threat-related amygdala activity and high executive control–related dorsolateral prefrontal cortex activity. ConclusionsThese brain activity patterns suggest that simultaneous consideration of their underlying cognitive processes—namely, threat processing and executive control—may be useful in strategies designed to mitigate the negative mental health consequences of childhood adversity.

Author response: Alterations of functional connectivity of the motor cortex in Fabry disease: An RS-fMRI study.

We thank Sechi et al. for the comments on our article.1 We agree that investigating the relationship between functional changes and disease course is a core issue for defining the role of functional imaging in both pathophysiology and clinical studies in Fabry disease (FD). The findings of Ortu et al.2 help define the role of the functional connectivity (FC) alterations in patients. Indeed, in their study,2 motor cortex hyperexcitability partly subsided when enzyme replacement therapy was started (although the small number of patients and the incomplete reversal of transcranial magnetic stimulation findings, possibly related to insufficient follow-up, does not allow for firm conclusions due to its complete reversibility). On the contrary, we found that resting-state–fMRI alterations were present in successfully treated patients, mitigating against the hypothesis that these changes may reflect reversible FD features.1 While our view is that “a direct relationship between motor cortex hyperexcitability…and present FC changes remains speculative,”1 longitudinal studies with suitable sample sizes assessing both FC and motor cortex excitability are needed. Only this approach will demonstrate if FC changes are related to a residual, nonreversible hyperexcitability, or if different neural circuit alterations are probed by the 2 techniques.

Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders.

A leading theory holds that neurodevelopmental brain disorders arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-dimensional model is rich enough to capture the multiple neural circuit alterations underlying brain disorders. Here, we combined computational simulations with analysis of in vivo two-photon Ca2+ imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: (1) The E/I imbalance model cannot account for joint alterations in the observed neural firing rates and correlations; (2) Neural circuit function is vastly more sensitive to changes in some cellular components over others; (3) The direction of circuit alterations in Fmr1 KO mice changes across development. These findings suggest that the basic E/I imbalance model should be updated to higher dimensional models that can better capture the multidimensional computational functions of neural circuits.

Alterations in Striatal Circuits Underlying Addiction-Like Behaviors.

Drug addiction is a severe psychiatric disorder characterized by the compulsive pursuit of drugs of abuse despite potential adverse consequences. Although several decades of studies have revealed that psychostimulant use can result in extensive alterations of neural circuits and physiology, no effective therapeutic strategies or medicines for drug addiction currently exist. Changes in neuronal connectivity and regulation occurring after repeated drug exposure contribute to addiction-like behaviors in animal models. Among the involved brain areas, including those of the reward system, the striatum is the major area of convergence for glutamate, GABA, and dopamine transmission, and this brain region potentially determines stereotyped behaviors. Although the physiological consequences of striatal neurons after drug exposure have been relatively well documented, it remains to be clarified how changes in striatal connectivity underlie and modulate the expression of addiction-like behaviors. Understanding how striatal circuits contribute to addiction-like behaviors may lead to the development of strategies that successfully attenuate drug-induced behavioral changes. In this review, we summarize the results of recent studies that have examined striatal circuitry and pathway-specific alterations leading to addiction-like behaviors to provide an updated framework for future investigations.

Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1-PAK3 signaling in neuroplasticity.

Although the pathogenesis of schizophrenia (SCZ) is proposed to involve alterations of neural circuits via synaptic dysfunction, the underlying molecular mechanisms remain poorly understood. Recent exome sequencing studies of SCZ have uncovered numerous single-nucleotide variants (SNVs); however, the majority of these SNVs have unknown functional consequences, leaving their disease relevance uncertain. Filling this knowledge gap requires systematic application of quantitative and scalable assays to assess known and novel biological functions of genes. Here we demonstrate loss-of-function effects of multiple rare coding SNVs found in SCZ subjects in the GIT1 (G protein-coupled receptor kinase interacting ArfGAP 1) gene using functional cell-based assays involving coexpression of GIT1 and PAK3 (p21 protein (Cdc42/Rac)-activated kinase 3). Most notably, a GIT1-R283W variant reported in four independent SCZ cases was defective in activating PAK3 as well as MAPK (mitogen-activated protein kinase). Similar functional deficits were found for a de novo SCZ variant GIT1-S601N. Additional assays revealed deficits in the capacity of GIT1-R283W to stimulate PAK phosphorylation in cultured hippocampal neurons. In addition, GIT1-R283W showed deficits in the induction of GAD1 (glutamate decarboxylase 1) protein expression. Extending these functional assays to 10 additional rare GIT1 variants revealed the existence of an allelic series with the majority of the SCZ case variants exhibiting loss of function toward MAPK activation in a manner correlated with loss of PAK3 activation. Taken together, we propose that rare variants in GIT1, along with other genetic and environmental factors, cause dysregulation of PAK3 leading to synaptic deficits in SCZ.

Distinct behavioral phenotypes in novel “fast” kindling-susceptible and “slow” kindling-resistant rat strains selected by stimulation of the hippocampal perforant path

Kindling is a phenomenon of activity-dependent neural circuit plasticity induced by repeated seizures that results in progressive permanent increases in susceptibility to epilepsy. As the permanent structural and functional modifications induced by kindling include a diverse range of molecular, cellular, and functional alterations in neural circuits, it is of interest to determine if genetic background associated with seizure-induced plasticity might also influence plasticity in neural circuitry underlying other behaviors. Outbred Sprague–Dawley (SD) rats were selected and bred for ~15 generations for “fast’ or “slow” rates of kindling development in response to stimulation of the perforant path input to the hippocampus. After 7–8 generations of selection and breeding, consistent phenotypes of “fast” and “slow” kindling rates were observed. By the 15th generation “fast” kindling rats referred to as Perforant Path Kindling Susceptible (PPKS) rats demonstrated a kindling rate of 10.7±1.1 afterdischarges (ADs) to the milestone of the first secondary generalized (Class V) seizure, which differed significantly from “slow” kindling Perforant Path Kindling Resistant (PPKR) rats requiring 25.5±2.0 ADs, and outbred SD rats requiring 16.8±2.5 ADs (p<0.001, ANOVA). Seizure-naïve adult PPKS and PPKR rats from offspring of this generation and age-matched adult outbred SD rats were compared in validated behavioral measures including the open field test as a measure of exploratory activity, the Morris water maze as a measure of hippocampal spatial memory, and fear conditioning as a behavioral paradigm of associative fear learning. The PPKS (“fast” kindling) strain with increased susceptibility to seizure-induced plasticity demonstrated statistically significant increases in motor exploratory activity in the open field test and reduced spatial learning the Morris water maze, but demonstrated normal fear conditioned learning comparable to outbred SD rats and the “slow” kindling-resistant PPKR strain. These results confirm that selection and breeding on the basis of responses to repeated pathway activation by stimulation can produce enduring modification of genetic background influencing behavior. These observations also suggest that genetic background underlying susceptibility or resistance to seizure-induced plasticity in hippocampal circuitry also differentially influences distinct behaviors and learning that depend on circuitry activated by the kindling selection process, and may have implications for associations between epilepsy, comorbid behavioral conditions, and cognition.

Integrated circuits and molecular components for stress and feeding: implications for eating disorders.

Eating disorders are complex brain disorders that afflict millions of individuals worldwide. The etiology of these diseases is not fully understood, but a growing body of literature suggests that stress and anxiety may play a critical role in their development. As our understanding of the genetic and environmental factors that contribute to disease in clinical populations like anorexia nervosa, bulimia nervosa and binge eating disorder continue to grow, neuroscientists are using animal models to understand the neurobiology of stress and feeding. We hypothesize that eating disorder clinical phenotypes may result from stress-induced maladaptive alterations in neural circuits that regulate feeding, and that these circuits can be neurochemically isolated using animal model of eating disorders.

Single-cell genetic expression of mutant GABAA receptors causing Human genetic epilepsy alters dendritic spine and GABAergic bouton formation in a mutation-specific manner.

Mutations in genes encoding for GABAA receptor subunits is a well-established cause of genetic generalized epilepsy. GABA neurotransmission is implicated in several developmental processes including neurite outgrowth and synapse formation. Alteration in excitatory/inhibitory synaptic activities plays a critical role in epilepsy, thus here we investigated whether mutations in α1 subunit of GABAA receptor may affect dendritic spine and GABAergic bouton formation. In particular, we examined the effects of three mutations of the GABRA1 gene (D219N, A322D and K353delins18X) that were found in a cohort of French Canadian families with genetic generalized epilepsy. We used a novel single-cell genetic approach, by preparing cortical organotypic cultures from GABRA1flox/flox mice and simultaneously inactivating endogenous GABRA1 and transfecting mutant α1 subunits in single glutamatergic pyramidal cells and basket GABAergic interneurons by biolistic transfection. We found that GABRA1−/− GABAergic cells showed reduced innervation field, which was rescued by co-expressing α1-A322D and α1-WT but not α1-D219N. We further found that the expression of the most severe GABRA1 missense mutation (α1-A322D) induced a striking increase of spine density in pyramidal cells along with an increase in the number of mushroom-like spines. In addition, α1-A322D expression in GABAergic cells slightly increased perisomatic bouton density, whereas other mutations did not alter bouton formation. All together, these results suggest that the effects of different GABAAR mutations on GABAergic bouton and dendritic spine formation are specific to the mutation and cannot be always explained by a simple loss-of-function gene model. The use of single cell genetic manipulation in organotypic cultures may provide a better understanding of the specific and distinct neural circuit alterations caused by different GABAA receptor subunit mutations and will help define the pathophysiology of genetic generalized epilepsy syndromes.

Seeking clues in brain development to explain the extraordinary evolution of language in humans

There has undoubtedly been a quantum leap forward in the evolution of cognitive processing in the human brain that has uniquely granted our species the use of syntactically complex language, however, the building blocks are present earlier in evolution suggesting that language may derive from our genes, and thus brains have evolved to embody a knowledge of Universal Grammar. Gene expression changes in development are the most likely to cause such macro-evolutionary alterations in neural circuits, and in this review I explore four areas of development predicted to be of importance. Firstly, there has been an increase in size and gyrification of the cerebral cortex. Secondly, there is increased connectivity between functional areas of the cortex, an expanded role for the subplate in guiding this process, and changes in synapse formation. Thirdly, the role of GABAergic interneurons in modulating functional connectivity has been enhanced and an elaboration in the developmental origins of interneurons may have led to an increased repertoire of functional subtypes. Finally, the development of lateralisation of language function is also briefly considered.

Same Brain Circuits Linked With Psychosis in Two Disorders

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessSame Brain Circuits Linked With Psychosis in Two DisordersJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:16 Jun 2014https://doi.org/10.1176/appi.pn.2014.6b8AbstractThe brains of schizophrenia patients and of those with bipolar disorder who experience psychotic episodes show similar connectivity patterns, which points to a common mechanism that may be associated with psychotic symptoms in the two disorders.Why is it that some individuals with bipolar disorder experience psychotic episodes, whereas others do not? It could be because the former have certain brain abnormalities in common with individuals who have schizophrenia, a new study suggests.The abnormalities concern the ventral anterior cingulate cortex (vAAC), a region in the prefrontal cortex thought to regulate emotional behavior through nerve connections with other areas of the brain—notably the orbitofrontal cortex, insula, amygdala, and hypothalamus.The lead researcher was Alan Anticevic, Ph.D., an assistant professor of psychiatry and psychology at Yale University. The results were published April 29 in Schizophrenia Bulletin.Many individuals with bipolar disorder also experience psychotic episodes. Functional disturbances in prefrontal cortex regions of the brain involved in affect and mood regulation—especially the vAAC—have been implicated in several bipolar disorder studies. Thus Anticevic and his team wanted to determine whether the vAAC might play a role in bipolar-related psychosis.Their cohort included 202 subjects—40 with bipolar disorder who were currently experiencing neither depression nor mania and who had never experienced psychotic episodes; 33 with bipolar disorder who were currently experiencing neither depression nor mania but who had experienced psychotic episodes; 56 demographically matched healthy controls, and 73 demographically matched subjects with schizophrenia. The researchers used brain imaging to compare the functional connectivity of the vAAC among the four subject groups.Compared with the control subjects, the bipolar-without-psychosis group showed significantly increased coupling of the vAAC to other brain regions, whereas the bipolar-with-psychosis subjects showed significantly decreased coupling of the vAAC to other brain regions. Moreover, the vAAC connectivity observed in schizophrenia subjects was significantly different from that found in the bipolar-without-psychosis subjects, but similar to that found in the bipolar-with-psychosis subjects. The findings remained the same even when the medications that subjects were using were taken into consideration.“The similarities in vAAC connectivity patterns in schizophrenia and psychotic bipolar disorder patients may suggest the existence of common mechanisms underlying psychotic symptoms in the two disorders,” Anticevic and his colleagues concluded.And these findings may have research implications, they noted, suggesting that researchers should “study neural circuit alterations across neuropsychiatric diagnoses, rather than studying narrowly predefined diagnostic categories.”“The findings reported here are striking and may be very important,” J. Raymond DePaulo Jr., M.D., a professor of psychiatry at Johns Hopkins University and a bipolar disorder expert said in an interview with Psychiatric News. “The findings are a step toward making functional sense of some of psychiatry’s diagnostic groupings and, if confirmed and extended, would contribute to the scientific substrate from which laboratory methods could be introduced into the psychiatric assessments of the future.”The research was funded by the National Institutes of Health, the Fulbright Foundation, and the Brain and Behavior Research Foundation. ■An abstract of “Ventral Anterior Cingulate Connectivity Distinguished Nonpsychotic Bipolar Illness From Psychotic Bipolar Disorder and Schizophrenia” can be accessed here. ISSUES NewArchived

An open system for automatic home-cage behavioral analysis and its application to male and female mouse models of Huntington's disease

Changes in routine mouse home-cage behavioral activities have been used recently to study alterations of neural circuits caused by genetic and environmental modifications and by drug administration. Nevertheless, automatic assessment of mouse home-cage behaviors remains challenging due to the cost of proprietary systems and to the difficulty in adjusting systems to different monitoring conditions. Here we present software for the automatic quantification of multiple facets of mouse home-cage behaviors, suitable for continuous 24h video monitoring. We used this program to assess behavioral changes in male and female R6/2 transgenic mouse models of Huntington's disease over a 10-week period. Consistent with the well-known progressive motor coordination deficits of R6/2 mice, their hanging, rearing, and climbing activity declined as the disease progressed. R6/2 mice also exhibited frequent disturbances in their resting activity compared to wild-type mice, suggesting that R6/2 mice are more restless and wakeful. Behavioral differences were seen earlier for male R6/2 mice than female R6/2 mice, and “behavioral signatures” based on multiple behaviors enabled us to distinguish male R6/2 mice from sex- and age-matched wild-type controls as early as 5 weeks of age. These results demonstrate that the automated behavioral classification software that we developed (“OpenCage”) provides a powerful tool for analyzing natural home-cage mouse behaviors, and for constructing behavioral signatures that will be useful for assessing therapeutic strategies. The OpenCage software is available under an open-source GNU General Public License, allowing other users to freely modify and extend it to suit their purposes.

Neural correlates of verbal semantic memory in patients with temporal lobe epilepsy

Functional imaging data suggest that the core network engaged in verbal semantic memory (SM) processing encompasses frontal and temporal lobe structures, with a strong left lateralization in normal right handers. The impact of long term temporal lobe epilepsy (TLE) on this network has only partly been elucidated. We studied verbal SM in 50 patients with chronic, intractable TLE (left TLE = 26, right TLE = 24) and 35 right handed normal controls using a verbal fMRI semantic decision paradigm. All patients had language lateralized to the left hemisphere, as verified by the intracarotid amobarbital procedure. Within and between group analyses showed remarkable, group-specific activation profiles. The control group activated frontal and temporal areas bilaterally, with a strong left predominance. Left TLE patients showed a shift of activations of left frontal and medial temporal areas to homologous regions in the right hemisphere. Furthermore, left TLE subjects utilized subcortical structures such as the thalamus and putamen to accomplish the verbal SM task. Contrastively, the activation pattern of right TLE patients resembled that of normal controls, but exhibited ‘hypofrontality’ with a shift from frontal to posterior regions in the temporal, parietal and occipital lobe. Our results show that chronic epileptic activity originating from temporal seizure foci is associated with an alteration of neural circuits which support semantic language processing and that side of seizure focus has a specific impact on the resulting activation network. These findings presumably result from morphological changes and from functional reorganization which are both inherent to chronic TLE.

Decreased chaos of midbrain dopaminergic neurons after serotonin denervation

Neuropharmacological investigations aimed at understanding the electrophysiological correlates between drug effect and action potential trains have usually been carried out with the analysis of firing rate and bursting activity. In this study, a selective alteration of neural circuits providing inputs to ventral tegmental area dopaminergic neurons has been produced, and the corresponding electrophysiological correlates have been investigated by nonlinear dynamical analysis. The nonlinear prediction method combined with Gaussian-scaled surrogate data has been used to show the chaotic structure in the time-series corresponding to the electrical activity of ventral tegmental area dopaminergic neurons, extracellularly recorded in vivo. A decrease in chaos of ventral tegmental area dopaminergic neurons was found in a group of rats lesioned with 5,7-dihydroxytryptamine, a neurotoxin which selectively destroys serotonergic terminals. The chaos content of ventral tegmental area dopaminergic neurons in the control group and the decrease of chaos in the lesioned group cannot be explained in terms of standard characteristics of neuronal activity (firing rate, bursting activity). Moreover, in the control group a positive correlation has been found between the density-power-spectrum of the interspike intervals and the chaos content measured by nonlinear prediction S score; this relation was lost in the lesioned group. It is concluded that the impaired serotonergic tone induced by 5,7-dihydroxytryptamine reduces the chaotic behaviour of the dopaminergic cell firing pattern, while retaining many standard interspike interval characteristics. The functional role of this behaviour in a neuronal coding problem context and the implications for the pathophysiology of some mental disorders are discussed.

γ-Aminobutyric acid contributes to modulation of cardiorespiratory control after chronic ventilatory loading

Diseases imposing chronic ventilatory loads may depress ventilation and cause chronic hypercapnia. This may be a result of mechanical loading imposed on pre-existing decreased respiratory drive or functional alteration of neural circuits involved in ventilatory control. To evaluate these possibilities, chronic resistive airway loading was imposed in rats via a circumferential tracheal band which tripled tracheal resistance (obstructed group). Sham surgery was performed in controls. After 8 weeks, animals were anesthetized (urethane) and tracheostomy performed relieving increased tracheal resistance. The ventral medullary surface (VMS) was exposed and the intermediate area (IA) identified. The integrated diaphragm EMG (EMG DI) was recorded. The obstructed group was hypercapnic while controls were eucapnic (P CO 2, 45.1±7.9 vs. 37.6±3.4 Torr; P<0.001). Respiratory rate (RR) remained lower in obstructed than in control animals despite relief of the resistive load by tracheostomy (58.5±5.1 vs. 75.4±5.4 bpm; P<0.05). Application of 1 mM bicuculline soaked pledgets (BIC) to the IA of the VMS significantly increased EMG DI in obstructed but not in control animals (27.5±5.5 vs. 5.2±4.4%; P<0.006). RR was unaffected. Mean arterial pressure increased with BIC in obstructed but not control animals (23.0±6.5 vs. 4.5±3.5%; P<0.02). These data suggest that alteration of cardiorespiratory control occurs during chronic resistive hypercapnic loading and that GABAergic neurons in the VMS participate in this adaptive response.

Functional alterations in neural circuits in Alzheimer's disease

While a correlation exists at the regional level between the distribution of neurofibrillary tangles and the predicted sites of brain dysfunction based on clinical and functional neuroimaging studies, the relationship between neurofibrillary tangles and neuronal dysfunction is poorly understood. Using cytochrome oxidase activity as a marker of neuronal functional activity, we found reductions in metabolic activity both in a hippocampal subfield with a high density of neurofibrillary tangles (CA1) as well as in subfields relatively spared (CA3, dentate granule cells). In contrast, we found no reduction in activity in primary visual cortex. Using in situ hybridization, we found a selective reduction in a mitochondrial-encoded cytochrome oxidase mRNA transcript with sparing of a nuclear-encoded transcript. These results suggest that the reduction in cytochrome oxidase activity in Alzheimer's disease brain may be related to an alteration in mitochondrial gene expression. The absence of a direct correlation between structural pathology and cytochrome oxidase activity suggests that neurons that remain structurally intact in Alzheimer's disease may nonetheless undergo substantial changes in metabolic activity.

Central auditory aging: GABA changes in the inferior colliculus.

Age-related hearing loss (presbycusis) is a complex state that reflects pathologic changes along the entire auditory neuraxis. Loss of speech understanding, decreased ability to localize sounds, and a decreased ability to detect and extract signals in noise are characteristic problems encountered by the elderly. Central (neural) presbycusis frequently results in a dramatic loss in speech understanding without a parallel change in pure-tone thresholds. In spite of evidence that suggests these deficits cannot be fully explained by peripheral changes alone, few studies have examined the neurochemical basis of central auditory dysfunction in aging. Age-related alterations in neural circuits involved in the processing of acoustic information could reflect changes in the synthesis, degradation, uptake, release, and receptor sensitivity of neurotransmitters, perhaps secondary to cell loss and/or progressive deafferentation. A series of studies designed to test this hypothesis has examined aging in the central auditory system of the F344 rate. Age-related changes associated with GABA neurotransmitter function in an important auditory midbrain structure, the inferior colliculus, have been investigated. These studies found: (1) decreased numbers of GABA immunoreactive neurons; (2) decreased basal levels (concentrations) of GABA; (3) decreased GABA release; (4) decreased glutamic acid decarboxylase activity; (5) decreased GABAB receptor binding; (6) decreased numbers of presynaptic terminals; and (7) subtle GABAA receptor binding changes. Collectively, these age-related changes suggest altered GABA neurotransmitter function in the IC. Identification of specific neurotransmitter changes in structures important in speech processing could eventually lead to the development of pharmacotherapy for selective types of age-related hearing loss.

Structural, neurochemical and behavioural consequences of neonatal blockade of NMDA receptor through chronic treatment with CGP 39551 or MK-801

Recent evidence suggests that NMDA receptors may be involved in survival of neurons and establishment of correct connectivity during development. We have treated rat pups from postnatal day 1 to 22 with daily s.c. injections of a competitive (CGP 39551) and a non-competitive (MK-801) antagonist of the NMDA receptor. Body weight of treated rats was decreased by 50–65% at postnatal day 24 and by 25–32% at 70 days of age. Brain weight was decreased by 16–24% at both ages. Among the different brain regions, the cerebellum and striatum appeared more decreased in size than the cortex and hippocampus. Only few minor, and in some cases transient, differences were measured in the cerebellum, the hippocampus and the cortex for a battery of neurochemical markers related to cholinergic, GABAergic and glutamatergic transmission as well as to astrocyte and oligodendrocyte activity. When tested in actometric cages from postnatal days 28 to 60, treated rats exhibited a dramatic increase of spontaneous locomotor activity which was maximal in 28-day-old animals (380% and 250% of control values in CGP 39551 and MK-801 groups, respectively) and was still significant at 60 days of age. Therefore, long-lasting alteration of motor behaviour is obtained by the schedule of chronic treatment adopted for the present experiments. Our results suggest that blockade of NMDA receptors during the critical period of brain maturation may result in permanent alteration of neural circuits.