Biomedical subjects

F Gonzalez-Lima

Publications and source records attributed to F Gonzalez-Lima.

At least 19 recordsLinked to original sources

PubMed2006

Methylene blue facilitates the extinction of fear in an animal model of susceptibility to learned helplessness.

The objectives were to (1) extend previous findings on fear extinction deficits in male congenitally helpless rats (a model for susceptibility to learned helplessness) to female congenitally helpless rats, and (2) attempt a therapeutic intervention with methylene blue, a metabolic enhancer that improves memory retention, to alleviate the predicted extinction deficits. In the first experiment, fear acquisition (four tone-shock pairings in operant chamber) was followed by extinction training (60 tones in open field). Congenitally helpless rats showed fear acquisition similar to controls but had dramatic extinction deficits, and did not display the gradual extinction curves observed in controls. Congenitally helpless rats demonstrated greater tone-evoked freezing as compared to controls in both the acquisition and extinction contexts one week after extinction training, and also in the extinction probe conducted one month later. In the second experiment (which began one month after the first experiment) congenitally helpless subjects were further exposed to tones for 5 days, each followed by 4 mg/kg methylene blue or saline IP, and had a fear renewal test in the acquisition context. Methylene blue administration improved retention of the extinction memory as demonstrated by significant decreases in fear renewal as compared to saline-administered congenitally helpless subjects. The impaired ability to extinguish fear to a traumatic memory in congenitally helpless rats supports the validity of this strain as an animal model for vulnerability to post-traumatic stress disorder, and this study further suggests that methylene blue may facilitate fear extinction as an adjunct to exposure therapy.

Analysis of Variance↗

PubMed2006

Chronic administration of 13-cis-retinoic acid increases depression-related behavior in mice.

Retinoid signaling plays a well-established role in neuronal differentiation, neurite outgrowth, and the patterning of the anteroposterior axis of the developing neural tube. However, there is increasing evidence that nutritional vitamin A status and retinoid signaling play an important role in the function of the adult brain. 13-Cis-retinoic acid (13-cis-RA) (isotretinoin or Accutane), a synthetic retinoid that is an effective oral treatment for severe nodular acne, has been linked with depression and suicide in patients. The purpose of this study was to test the hypothesis that chronic administration of 13-cis-RA would lead to depression-related behaviors in mice. Young, adult male mice received 13-cis-RA (1 mg/kg) by daily intraperitoneal injection for 6 weeks. This treatment paradigm produced plasma levels of 13-cis-RA that are comparable to those reported in human patients taking Accutane. In both the forced swim test and the tail suspension test, we found that 13-cis-RA-treated mice spent significantly more time immobile compared to vehicle-treated controls. In the open field test, there was no change in anxiety-related behavior in 13-cis-RA-treated mice. Furthermore, chronic administration of 13-cis-RA did not impair locomotion in either the open field or the rotarod test. Taken together, these results suggest that administration of 13-cis-RA increases depression-related behaviors in mice.

Animals↗

PubMed2006

Methylene blue prevents neurodegeneration caused by rotenone in the retina.

An experimental optic neuropathy model was used to test the hypothesis that methylene blue may protect the retinal ganglion cell layer from neurodegeneration caused by rotenone. Rotenone is a widely used pesticide that inhibits complex I, the first enzyme of the mitochondrial respiratory chain. Complex I dysfunction is linked to the degeneration of retinal ganglion cells in Leber's optic neuropathy. Methylene blue is a reduction-oxidation agent that can act as a powerful antioxidant and also as an enhancer of the electron transport chain, preventing formation of mitochondrial oxygen free radicals and promoting oxygen consumption. The neurodegeneration of the retina was studied in mice with intravitreal microinjection of rotenone alone, or in combination with increasing doses of methylene blue, in one eye, and the vehicle in the contralateral control eye. The effect of rotenone and rotenone plus methylene blue was investigated using two histological stains, complex I and Nissl, and two measurements, morphometric layer thickness and non-biased stereological cell counts. Rotenone induced neurodegeneration in the retinal ganglion cell layer 24 h after injection, as indicated by significant reductions in both the thickness and cell numbers of the retinal ganglion cell layer of eyes microinjected with rotenone as compared to the control eyes. This neurodegeneration was prevented in a dose dependent manner by the injection of methylene blue along with rotenone. It was concluded that rotenone-induced degeneration in the ganglion cell layer can be prevented by intravitreal injection of methylene blue. In vitro experiments showed that methylene blue is both a powerful antioxidant as well as an enhancer of cellular oxygen consumption and is able to reverse the oxidative stress and decrease in oxygen consumption induced by rotenone in brain homogenates. The findings suggest that methylene blue may be a promising neuroprotective agent in optic neuropathy and perhaps other neurodegenerative diseases caused by mitochondrial dysfunction.

Analysis of Variance↗

PubMed2006

Neurodegeneration produced by rotenone in the mouse retina: a potential model to investigate environmental pesticide contributions to neurodegenerative diseases.

Rotenone is a widely used pesticide and fish toxin that inhibits complex I of the mitochondrial respiratory chain. Complex I dysfunction is linked to the degeneration of retinal ganglion cells in Leber's optic neuropathy. To study the association between environmental mitochondrial toxin exposure and neurodegeneration, mice were intravitreally microinjected with rotenone in one eye and with the vehicle dimethyl sulfoxide in the contralateral eye, as a within-subject control. The retinal ganglion cell layer (GCL) of eyes injected with rotenone became significantly thinner than that of the control eyes after 24 h, but not as early as 0.5 h. This reduction was observed using complex I histochemistry and with Nissl staining of cell bodies. After 24 h, retinal nerve fiber layer thickness was reduced by 89% and the number of GCL cells was reduced by 21% in rotenone-treated eyes. Cellular morphometric data (soma area, perimeter, and diameter) did not show overall differences, but there was a preferential reduction in the proportion of larger cells. Therefore, the reduction in GCL thickness 24 h after rotenone microinjection could be accounted for by cell loss and nerve fiber shrinkage, but not by overall soma size change. Rotenone-induced degeneration of the ganglion cell layer may be used as a convenient way to (1) evaluate mechanisms and treatments for the neurodegeneration produced by mitochondrial dysfunction and (2) investigate environmental pesticide contributions to neurodegenerative diseases.

Animals↗

PubMed2006

Brain activity associated with fear renewal.

This is the first mapping study of the brain activity associated with the renewal of an extinguished conditioned response. Rats were given radiolabeled fluorodeoxyglucose, a glucose analog, to map brain effects of an extinguished tone during context-dependent renewal of conditioned fear. A tone conditioned stimulus was paired with a footshock unconditioned stimulus in a first context, followed by conditioned response extinction in a second context and conditioned response renewal in a third context. Control rats were treated identically, except that tone and shock were presented pseudorandomly. Compared with control subjects, rats with conditioned response renewal had increased tone-evoked fluorodeoxyglucose uptake in the auditory system (auditory cortex, medial geniculate, inferior colliculus and lateral lemniscal nuclei), as well as somatic and visceral sensory nuclei (external cuneate, spinal trigeminal, solitary tract and vestibular nuclei). In addition, perirhinal cortex, anterior lateral hypothalamus and ventrolateral periaqueductal gray showed conditioned response renewal effects. Brain-behavior correlations indicated that the activity of the external cuneate nucleus strongly predicted the conditioned response in the renewal group. It is suggested that context-dependent fear renewal is associated with (1) tone-evoked activation of the excitatory conditioned stimulus representation in the auditory system, (2) associative activation of the unconditioned stimulus representation in somatic and visceral sensory nuclei in the absence of the unconditioned stimulus, and (3) neural activation of the perirhinal cortex, hypothalamus and periaqueductal gray. These findings support Pavlov's stimulus-substitution theory as a neural mechanism contributing to the renewal effect.

Analysis of Variance↗

PubMed2005

Behavioral characteristics of rats predisposed to learned helplessness: reduced reward sensitivity, increased novelty seeking, and persistent fear memories.

The congenitally helpless rat strain, which was selectively bred for increased susceptibility to learned helplessness, may model the predisposition to affective disorders, including depression and post-traumatic stress disorder. Other than the selected trait, the behavior of this strain is not well characterized. In this study, we assessed congenitally helpless rats on several behavioral tests. First, we assessed reward sensitivity by measuring their consumption of a 5% sucrose solution. Next, we assessed exploratory behavior and fearfulness in both a novel and familiar open field, and in a light-dark test. Finally, we assessed fear conditioning by exposing the animals to 4 tone-shock pairs on 1 day (acquisition) and then presenting 60 tones over the next 2 days (extinction). Compared to normal Sprague-Dawley controls, congenitally helpless rats showed less consumption of the sucrose solution and more exploratory behavior in the novel, but not the familiar, open fields. They also showed less fearfulness in the light-dark test, but more conditioned freezing to the tone predicting shock. Moreover, this freezing was resistant to extinction; congenitally helpless rats not only failed to show a fear decrement during extinction, but actually showed increased fear, a phenomenon termed "paradoxical enhancement." Thus, congenitally helpless rats appear to have a behavioral phenotype characterized by reduced sensitivity to reward, increased drive to explore novel environments, and increased propensity to form and maintain fear-associated memories. This behavioral phenotype is discussed as resembling the personality of humans vulnerable to post-traumatic stress disorder.

Animals↗

PubMed2005

Effects of maternal separation, early handling, and standard facility rearing on orienting and impulsive behavior of adolescent rats.

Effects of maternal separation in rats have been extensively investigated, but no studies have examined its effects in rat adolescence. We examined the effects of neonatal infant-mother separation (MS) for 6h/day and early handling (EH) for 10 days during the first 2 weeks of life by comparing MS and EH groups to standard facility reared (SFR) controls. At adolescence, the animals were evaluated in a novel and familiar open-field, the light-dark box, and the sucrose consumption test. Behavioral indices included orienting behavior (rearing frequency and duration), impulsive behavior (movement velocity and risk taking by entering the center of the open field or the light compartment of the light-dark box), hyperactivity (ambulatory distance and stereotypic movement), and reward-seeking behavior (sucrose drinking time). The prolonged MS during the first 2 weeks of life resulted in decreased orienting behavior and increased impulsive behavior in adolescence. Measures of ambulatory and stereotypic movements showed that MS rats were hyperactive in the novel environment whereas EH rats were less active overall. The impulsive/hyperactive phenotype produced by this MS protocol may provide a useful animal model to investigate the neurological basis for the similar behavioral phenotype found in attention deficit/hyperactivity disorder.

Age Factors↗

PubMed2005

Memory facilitation by methylene blue: dose-dependent effect on behavior and brain oxygen consumption.

Methylene blue administered post-training improves memory retention in avoidance and appetitive tasks, and restores spatial memory impaired by an inhibitor of cytochrome oxidase. Methylene blue may improve memory retention by increasing brain oxygen utilization. We investigated which doses improve memory without nonspecific behavioral effects, and whether methylene blue enhances brain oxygen consumption. Different doses were evaluated 24 h after administration in wheel running, feeding, open field habituation and object recognition tests. The 1-10 mg/kg methylene blue-treated rats were not different from saline-treated rats in locomotion or feeding behavior. The 50-100 mg/kg doses decreased running wheel behavior. The 4 mg/kg dose improved behavioral habituation and object memory recognition. Dose-dependent effects of methylene blue on brain oxygen consumption revealed that low concentrations increased brain oxygen consumption in vitro and 24 h after in vivo administration. Therefore, methylene blue doses that increase brain oxygen consumption also facilitate memory retention.

Analysis of Variance↗

PubMed2005

Neuregulin-1 immunoglobulin-like domain mutant mice: clozapine sensitivity and impaired latent inhibition.

Genetic and behavioral studies in humans and mouse mutants have implicated the gene encoding neuregulin-1 (Nrg-1) as a candidate susceptibility gene for schizophrenia. We examined the behavior of mice heterozygous for a mutation in neuregulin-1's immunoglobulin (Ig)-like domain (Ig-nrg-1 mice). We found that these animals displayed behaviors related to a schizophrenia-like phenotype, such as clozapine suppression of open-field and running wheel activity and impaired latent inhibition. Contrary to findings with other nrg-1 mutants, Ig-nrg-1 mice did not exhibit significantly elevated locomotion relative to littermate controls. These results suggest that Ig-Nrg-1's contribute to some - but not all - aspects of the schizophrenia-like phenotype of nrg-1 mutants, and further support nrg-1 as a candidate gene for schizophrenia.

Animals↗

PubMed2005

Behavioral correlates of differences in neural metabolic capacity.

Cytochrome oxidase is a rate-limiting enzyme in oxidative phosphorylation, the major energy-synthesizing pathway used by the central nervous system, and cytochrome oxidase histochemistry has been extensively utilized to map changes in neural metabolism following experimental manipulations. However, the value of cytochrome oxidase activity in predicting behavior has not been analyzed. We argue that this endeavor is important because genetic composition and embryonic environment can engender differences in baseline neural metabolism in pertinent neural circuits, and these differences could represent differences in the degree to which specific behaviors are 'primed.' Here we review our studies in which differences in cytochrome oxidase activity and in behavior were studied in parallel. Using mammalian and reptilian models, we find that embryonic experiences that shape the propensity to display social behaviors also affect cytochrome oxidase activity in limbic brain areas, and elevated cytochrome oxidase activity in preoptic, hypothalamic, and amygdaloid nuclei correlates with heightened aggressive and sexual tendencies. Selective breeding regimes were used to create rodent genetic lines that differ in their susceptibility to display learned helplessness and in behavioral excitability. Differences in cytochrome oxidase activity in areas like the paraventricular hypothalamus, frontal cortex, habenula, septum, and hippocampus correlate with differences in susceptibility to display learned helplessness, and differences in activity in the dentate gyrus and perirhinal and posterior parietal cortex correlate with differences in hyperactivity. Thus, genetic and embryonic manipulations that engender specific behavioral differences produce specific neurometabolic profiles. We propose that knowledge of neurometabolic differences can yield valuable predictions about behavioral phenotype in other systems.

Aggression↗

PubMed2004

Brain differences in newborn rats predisposed to helpless and depressive behavior.

Inborn brain differences in metabolic capacity were mapped in congenitally helpless rats, a genetically selected strain predisposed to show helpless and depressive behavior. There are a number of brain regions showing abnormal metabolism in adult congenitally helpless rats. Some of these alterations may be innate while others may be due to environmental factors, such as maternal care and postnatal stress. To identify which brain structures show innate differences, brains of newborn rats from congenitally helpless and non-helpless strains were compared using cytochrome oxidase histochemistry, an endogenous marker of regional metabolic capacity. A smaller subset of regions affected in adults showed significantly less metabolic activity in the newborn brains, including paraventricular hypothalamus, habenula, hippocampus, subiculum, lateral septal nucleus, anterior cingulate cortex, infralimbic cortex, and medial orbitofrontal cortex. A covariance analysis further revealed a striking reduction of functional connectivity in the congenitally helpless brain, including a complete decoupling of limbic forebrain regions from midbrain/diencephalic regions. This pattern of brain metabolism suggests that helplessness vulnerability is linked to altered functioning of limbic networks that are key to controlling the hypothalamic-pituitary-adrenal axis. This implies that vulnerable animals have innate deficits in brain systems that would normally allow them to cope with stress, predisposing them in this manner to more readily develop helpless and depressive behaviors.

Analysis of Variance↗

PubMed2004

Behavioral effects of metyrapone on Pavlovian extinction.

This is the first study of the action of metyrapone on Pavlovian extinction. Pavlovian acquisition memory can be impaired when 50 mg/kg metyrapone, a corticosterone synthesis inhibitor, is injected 90 min before training. It was hypothesized that the same treatment given before extinction may also impair Pavlovian extinction memory, and thereby facilitate recovery of the extinguished behavior. This study examined the behavioral effects of 50 mg/kg metyrapone on the extinction of conditioned freezing following Pavlovian conditioning of tone (CS) and footshock (US). On days 1-2, mice were habituated to the training context. On days 4-5, mice received 4 tone-shock pairings per day. On day 6, metyrapone or saline was injected s.c. 90 min before an extinction session with 60 tone presentations. Probe sessions with 4 tones were conducted in the extinction context on day 7 and in the acquisition context on day 9. Metyrapone treatment did not affect performance during extinction or pre-CS freezing behavior. But metyrapone-treated animals showed greater conditioned freezing when tested with the tone the day after extinction in the extinction context (spontaneous recovery) and 3 days after extinction in the acquisition context (renewal effect). It was concluded that 50 mg/kg metyrapone did not affect extinction performance, but it effectively facilitated the subsequent recovery of the extinguished behavior. This effect may be explained by an impairment of the consolidation of the Pavlovian extinction memory. This interpretation is consistent with previous studies showing that metyrapone may interfere with memory consolidation for a variety of learned responses.

Animals↗

PubMed2004

Methylene blue improves brain oxidative metabolism and memory retention in rats.

Methylene blue (MB) increases mitochondrial oxygen consumption and restores memory retention in rats metabolically impaired by inhibition of cytochrome c oxidase. This study tested two related hypotheses using biochemical and behavioral techniques: (1) that low-level MB would enhance brain cytochrome c oxidation, as tested in vitro in brain homogenates and after in vivo administration to rats and (2) that corresponding low-dose MB would enhance spatial memory retention in normal rats, as tested 24 h after rats were trained in a baited holeboard maze for 5 days with daily MB posttraining injections. The biochemical in vitro studies showed an increased rate of brain cytochrome c oxidation with the low but not the high MB concentrations tested. The in vivo administration studies showed that the corresponding MB low dose (1 mg/kg) increased brain cytochrome c oxidation 24 h after intraperitoneal injection, but not after 1 or 2 h postinjection. In the behavioral studies, spatial memory retention in probe trials (percentage of visits to training-baited holes compared to total visits) was significantly better for MB-treated than saline control groups (66% vs. 31%). Together the findings suggest that low-dose MB enhances spatial memory retention in normal rats by increasing brain cytochrome c oxidase activity.

Animals↗

PubMed2003

Metabolic mapping of mouse brain activity after extinction of a conditioned emotional response.

Metabolic mapping with fluorodeoxyglucose (FDG), a radiolabeled glucose analog, was used to assess regional activity changes in the mouse brain that result from extinction of a conditioned emotional response (CER). In the extinction group, Pavlovian tone-foot shock conditioning, followed by repeated tone-alone presentations, resulted in the reduction of the CER (freezing behavior). A second group underwent CER acquisition alone (nonextinction group), and a third group showed no CER after pseudorandom training. Then mice were injected with FDG, and tone-evoked brain activity was mapped. In the auditory system, increased activity resulted from the associative effects of acquisition training. Effects common to extinction and nonextinction groups, presumably reflecting the tone-foot shock association independently of CER expression, were found in the medial geniculate, hippocampus, and subiculum. In the extinction group, a major finding was the elevated activity in prefrontal cortex regions. In addition, brain-behavior correlations between FDG uptake and freezing behavior confirmed that subjects with higher prefrontal activity were more successful at inhibiting the CER. Interregional activity correlations showed extensive functional coupling across large-scale networks in the extinction group. The increased activity of the prefrontal cortex and its negative interactions with other regions within the extinction group suggest a functional network inhibiting the CER composed of prefrontal cortex, medial thalamus, auditory, and hippocampal regions. This is the first time that such a functional network resulting from Pavlovian extinction has been demonstrated, and it supports Pavlov's original hypothesis of extinction as the formation of cortical inhibitory circuits, rather than unlearning or reversal of the acquisition process.

Acoustic Stimulation↗

PubMed2003

Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior.

Congenitally helpless rats have been selectively bred to display an immediate helpless response to stress in order to model hereditary brain differences that contribute to depression vulnerability. Differences in regional brain metabolism between congenitally helpless and non-helpless rats were investigated using quantitative cytochrome oxidase histochemistry. The results indicated that congenitally helpless rats had 64-71% elevated metabolism in the habenula and a 25% elevation in the related interpeduncular nucleus. In contrast, helpless rats had 28% reduced metabolism in the ventral tegmental area (VTA) and 14-16% reductions in the basal ganglia and basolateral and central amygdala. The opposite metabolic changes in the habenula and ventral tegmental area may be especially important for determining the congenitally helpless rat's global pattern of brain activity, which resembles the metabolic activity pattern produced by dopamine antagonism.

Animals↗

PubMed2003

Brain systems underlying susceptibility to helplessness and depression.

There has been a relative lack of research into the neurobiological predispositions that confer vulnerability to depression. This article reviews functional brain mappings from a genetic animal model, the congenitally helpless rat, which is predisposed to develop learned helplessness. Neurometabolic findings from this model are integrated with the neuroscientific literature from other animal models of depression as well as depressed humans. Changes in four major brain systems are suggested to underlie susceptibility to helplessness and possibly depression: (a) an unbalanced prefrontal-cingulate cortical system, (b) a dissociated hypothalamic-pituitary-adrenal axis, (c) a dissociated septal-hippocampal system, and (d) a hypoactive brain reward system, as exemplified by a hypermetabolic habenula-interpeduncular nucleus pathway and a hypometabolic ventral tegmental area-striatum pathway. Functional interconnections and causal relationships among these systems are considered and further experiments are suggested, with theoretical attention to how an abnormality in any one system could affect the others.

Animals↗

PubMed2002

Methylene blue restores spatial memory retention impaired by an inhibitor of cytochrome oxidase in rats.

Cytochrome oxidase is the mitochondrial enzyme that catalyzes the utilization of oxygen for the electron transport chain during cellular respiration. Chronic subcutaneous infusion of sodium azide, an inhibitor of cytochrome oxidase, produced a spatial memory retention deficit in rats in a holeboard maze. Methylene blue, which has been shown to increase oxygen consumption in vitro, was used to restore mitochondrial electron transport in order to facilitate memory consolidation. Administration of 1 mg/kg methylene blue after training, during the memory consolidation period, completely restored the memory retention impaired by the inhibitor of cytochrome oxidase. This suggests that methylene blue may compensate for impaired mitochondrial respiration and improve spatial memory retention. Memory retention deficits found in some neurodegenerative diseases may be improved by drugs targeting impaired mitochondrial respiration.

Analysis of Variance↗

PubMed2002

Mouse model of optic neuropathy caused by mitochondrial complex I dysfunction.

We developed a mouse model of optic neuropathy caused by mitochondrial complex I dysfunction by intravitreal administration of rotenone, a complex I inhibitor, in CBA/J mice. Retinal thickness was measured in sections stained histochemically for complex I enzymatic activity. The retinal ganglion cell layer of eyes injected with rotenone was significantly thinner than that of the control eyes injected with the vehicle dimethyl sulfoxide at 1, 24, and 48-h survival time groups. The largest reduction was 43% at 24-h post-injection. This effect is consistent with the degeneration of retinal ganglion cells in Leber's hereditary optic neuropathy. This is the first animal model of optic neuropathy caused by mitochondrial dysfunction, and it could be used as a quick and convenient way to test new treatments for mitochondrial neurodegenerative diseases.

Animals↗