cNLH Rats Research Articles

Synaptic abnormalities in the infralimbic cortex of a model of congenital depression.

Multiple lines of evidence suggest that disturbances in excitatory transmission contribute to depression. Whether these defects involve the number, size, or composition of glutamatergic contacts is unclear. This study used recently introduced procedures for fluorescence deconvolution tomography in a well-studied rat model of congenital depression to characterize excitatory synapses in layer I of infralimbic cortex, a region involved in mood disorders, and of primary somatosensory cortex. Three groups were studied: (1) rats bred for learned helplessness (cLH); (2) rats resistant to learned helplessness (cNLH); and (3) control Sprague Dawley rats. In fields within infralimbic cortex, cLH rats had the same numerical density of synapses, immunolabeled for either the postsynaptic density (PSD) marker PSD95 or the presynaptic protein synaptophysin, as controls. However, PSD95 immunolabeling intensities were substantially lower in cLH rats, as were numerical densities of synapse-sized clusters of the AMPA receptor subunit GluA1. Similar but less pronounced differences (comparable numerical densities but reduced immunolabeling intensity for PSD95) were found in the somatosensory cortex. In contrast, non-helpless rats had 25% more PSDs than either cLH or control rats without any increase in synaptophysin-labeled terminal frequency. Compared with controls, both cLH and cNLH rats had fewer GABAergic contacts. These results indicate that congenital tendencies that increase or decrease depression-like behavior differentially affect excitatory synapses.

Enhanced mGlu5-receptor dependent long-term depression at the Schaffer collateral-CA1 synapse of congenitally learned helpless rats

Alterations of the glutamatergic system have been implicated in the pathophysiology and treatment of major depression. In order to investigate the expression and function of mGlu5 receptors in an animal model for treatment-resistant depression we used rats bred for congenital learned helplessness (cLH) and the control strain, bred for resistance against inescapable stress, congenitally.not learned helpless rats (cNLH). Western blot analysis showed an increased expression of mGlu5 (but not mGlu1a) receptors in the hippocampus of cLH rats, as compared with control cNLH rats. We also examined mGlu1/5 receptor signaling by in vivo measurement of DHPG-stimulated polyphosphoinositides hydrolysis. Stimulation of 3H-inositolmonophosphate formation induced by i.c.v. injection of DHPG was enhanced by about 50% in the hippocampus of cLH rats. Correspondingly, DHPG-induced long-term depression (LTD) at Schaffer collateral/CA1 pyramidal cell synapses was amplified in hippocampal slices of cLH rats, whereas LTD induced by low frequency stimulation of the Schaffer collaterals did not change. Moreover, these effects were associated with decreased basal dendritic spine density of CA1 pyramidal cell in cLH rats.These data raise the attractive possibility that changes in the expression and function of mGlu5 receptors in the hippocampus might underlie the changes in synaptic plasticity associated with the depressive-like phenotype of cLH rats. However, chronic treatment of cLH rats with MPEP did not reverse learned helplessness, indicating that the enhanced mGlu5 receptor function is not the only player in the behavioral phenotype of this genetic model of depression.This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’.

Cognitive aspects of congenital learned helplessness and its reversal by the monoamine oxidase (MAO)-B inhibitor deprenyl

Cognitive processes are assumed to change with learned helplessness, an animal model of depression, but little is known about such deficits. Here we investigated the role of cognitive and related functions in selectively bred helpless (cLH, n = 10), non-helpless (cNLH, n = 12) and wild type (WT, n = 8) Sprague Dawley rats. The animals were exposed to an open field for 10 min on each of two test days. On the third day, an object exploration paradigm was carried out. The animals were later tested for helplessness. Both cLH and cNLH rats were more active than WTs on the first day in the open field. Over trials, cNLH and WT rats lowered their activity less than cLH rats. This resistance-to-habituation co-varied with a resistance to develop helplessness. In cLH rats, higher ‘anxiety’ or less time spent in the center of the open field co-varied with severe helplessness. In WTs, a greater reactivity to novel objects and to a spatially relocated object predicted lower levels of helplessness. In cLH rats ( n = 4–5 per group), chronic treatment with a high dose of the monoamine oxidase (MAO)-B inhibitor deprenyl (10 mg/kg; i.p.), an anti-Parkinson, nootropic and antidepressant drug, attenuated helplessness. Remarkably, helplessness reversal required the experience of repeated test trials, reminiscent of a learning process. Chronic deprenyl (10 mg/kg; i.p.) did not alter locomotion/exploration or ‘anxiety’ in the open field. In conclusion, helplessness may be related to altered mechanisms of reinforcement learning and working memory, and to abnormalities in MAO-A and/or MAO-B functioning.

Reduced sensitivity to sucrose in rats bred for helplessness: a study using the matching law

Anhedonia is a core symptom of depression. As it cannot be directly assessed in rodents, anhedonia is usually inferred from a reduced consumption of, or preference for, a reinforcer. In the present study we tried to improve the measurement of anhedonia by performing a detailed preference analysis based on the generalized matching law and tested its sensitivity in rats congenitally prone (cLH) or resistant (cNLH) to learned helplessness. According to the current interpretation of learned helplessness as a model for depression, a reduction in the rewarding properties of sucrose in cLH rats was hypothesized. Our results revealed that the 'preference allocation' index provided by this test, but not the traditional measures of sucrose consumption or preference over water, was significantly lower in cLH rats, and was correlated with the helpless behaviour as measured in an escape procedure. Therefore, it is clear that more subtle preference measures provided by the analysis of choice using the matching law principles are more sensitive and discriminative than those based on consumption of, or preference for, a single concentration of sucrose over water. Moreover, our data are in agreement with the proposed relationship between helplessness and sucrose preference, and support the usefulness of the cLH and cNLH rats as a model of depression.

Voluntary alcohol intake in two rat lines selectively bred for learned helpless and non-helpless behavior

A high comorbidity between depression and alcoholism has been reported in several studies, but the mechanisms underlying this relationship remain unknown. We tested whether learned helplessness in rats as a model for depression is associated with enhanced alcohol intake and relapse behavior. Congenital learned helplessness (cLH) and congenital non-learned helplessness (cNLH) rats were selectively bred for differences in an escape paradigm. Sucrose preference was tested at the first hour of the dark phase. In order to study an association with alcohol drinking behavior, rats underwent a free-choice procedure with access to water, and 5% and 20% alcohol solutions for 6 weeks. After acquisition of alcohol drinking behavior, the alcohol deprivation effect (ADE) was assessed. Sensitivity to the sedative-hypnotic effect of alcohol was measured by loss of the righting reflex. cLH rats showed significantly lower preference for sucrose solutions during the second half hour of the dark phase than cNLH rats. Alcohol intake of male cLH rats was not significantly different from that of male cNLH rats. In contrast, cLH female rats consumed higher amounts of alcohol than female cNLH rats. The ADE was more pronounced in female animals, although the magnitude of the ADE was similar in both cNLH and cLH female rats. The time to regain the righting reflex was significantly higher in both male and female cLH rats than in cNLH rats. In summary, these data suggest that an inborn depressive-like behavior in female rats is associated with enhanced alcohol intake.

Rats with congenital learned helplessness respond less to sucrose but show no deficits in activity or learning

Inbred rat strains for congenital learned helplessness (cLH) and for congenital resistance to learned helplessness (cNLH) were investigated as a model to study genetic predisposition to major depression. Congenitally helpless rats respond less to sucrose under a progressive ratio schedule. This is not confounded by locomotor hypoactivity: in contrast, cLH rats show a slight hyperactivity during the first 5 min of an open field test. cLH rats acquire operant responding to sucrose as readily as cNLH rats and exhibit normal memory acquisition and retrieval in the Morris water maze, thus ruling out general learning deficits as the cause of the decreased response to sucrose. Reduced total responses and reduced breaking points for sucrose in the cLH strain argue for anhedonia, which is an analogue to loss of pleasure essential for the diagnosis of major depressive episodes, and thus confirm the validity of congenitally learned helpless rats as a model of major depression.

Brain-derived-neurotrophic-factor (BDNF) stress response in rats bred for learned helplessness.

Stress-induced elevation of glucocorticoids is accompanied by structural changes and neuronal damage in certain brain areas. This includes reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus which can be prevented by chronic electroconvulsive seizures and antidepressant drug treatment. In the last years we have bred two strains of rats, one which reacts with congenital helplessness to stress (cLH), and one which congenitally does not acquire helplessness when stressed (cNLH). After being selectively bred for more than 40 generations these strains have lost their behavioural plasticity including their sensitivity to antidepressant treatment. We show here that in cLH rats, acute immobilization stress does not induce a reduction of BDNF expression in the hippocampus which is observed in Sprague--Dawley and cNLH rats. All animals tested exhibited elevated corticosterone levels when stressed, an indication, that in cLH rats regulation of BDNF expression in the hippocampal formation is uncoupled from corticosterone increase induced through stress. This may explain the lack of adaptive responses in this strain.

233. Elevated thyroid hormone levels in brains of congenital learned helpless rats

Learned helplessness has been well characterized as a model of depression. Since alterations in brain thyroid hormone levels have been hypothesized to occur in depressive illness, the present study examined brain thyroid hormone levels in rats selectively bred (42 generations) for increased susceptibility to learned helpless behavior (congenital helpless rats, cLH) and in their non-helpless (cNLH) counterparts. Brains from eight stress-naive female rats from each group were examined. A small, but significant, elevation in whole-brain levels of thyroxine was found in cLH rats as compared to cNLH rats (12%, p < 0.04). Congenital helpless rats also showed a 32% increase in whole brain triiodothyronine levels compared to cNLH rats, but this difference was not statistically significant. Activity of type II deiodinase (which converts thyroxine to triiodothyronine in brain) was not significantly different between the two groups. These results provide the first indication that brain thyroid hormone levels are elevated in congenital helpless rats and the absence of any exposure to stressful stimulation. The data further suggests that increased brain thyroid hormone levels may contribute to depressive-like disorders.

Elevated plasma norepinephrine and DOPA spillover in repeatedly stressed rats

Cognitive processes are assumed to change with learned helplessness, an animal model of depression, but little is known about such deficits. Here we investigated the role of cognitive and related functions in selectively bred helpless (cLH, n = 10), non-helpless (cNLH, n = 12) and wild type (WT, n = 8) Sprague Dawley rats. The animals were exposed to an open field for 10 min on each of two test days. On the third day, an object exploration paradigm was carried out. The animals were later tested for helplessness. Both cLH and cNLH rats were more active than WTs on the first day in the open field. Over trials, cNLH and WT rats lowered their activity less than cLH rats. This resistance-to-habituation co-varied with a resistance to develop helplessness. In cLH rats, higher ‘anxiety’ or less time spent in the center of the open field co-varied with severe helplessness. In WTs, a greater reactivity to novel objects and to a spatially relocated object predicted lower levels of helplessness. In cLH rats (n = 4–5 per group), chronic treatment with a high dose of the monoamine oxidase (MAO)-B inhibitor deprenyl (10 mg/kg; i.p.), an anti-Parkinson, nootropic and antidepressant drug, attenuated helplessness. Remarkably, helplessness reversal required the experience of repeated test trials, reminiscent of a learning process. Chronic deprenyl (10 mg/kg; i.p.) did not alter locomotion/exploration or ‘anxiety’ in the open field. In conclusion, helplessness may be related to altered mechanisms of reinforcement learning and working memory, and to abnormalities in MAO-A and/or MAO-B functioning.