Regulation of extracellular serotonin levels and brain-derived neurotrophic factor in rats with high and low exploratory activity.

Serotonin (5-HT) system has a significant role in anxiety- and depression-related states and may be influenced by brain-derived neurotrophic factor (BDNF). This study examined extracellular 5-HT levels and expression of BDNF in rats with persistently low or high levels of exploratory activity (LE and HE, respectively). Baseline extracellular levels of 5-HT as assessed by in vivo microdialysis in conscious animals were similar in both groups in medial prefrontal cortex (PFC) and dentate gyrus (DG). No differences were found in parachloroamphetamine-induced 5-HT release in either region. However, LE animals had significantly higher levels of 5-HT transporter (5-HTT) binding in PFC and a larger increase in extracellular 5-HT levels after administration of citalopram (1 microM) into this area by retrograde dialysis. No difference in 5-HTT levels was found in hippocampus, while perfusion with citalopram was accompanied by a greater increase in extracellular 5-HT in the HE group in this brain region. LE-rats had higher levels of BDNF mRNA in the PFC but not hippocampus. In contrast, levels of nerve growth factor mRNA were similar in these brain regions of LE- and HE-rats. The differential regulation of 5-HT-ergic system in LE- and HE-rats in PFC and hippocampus may form the basis for their distinct anxiety-related behaviours.

Rat behavior after chronic variable stress and partial lesioning of 5-HT-ergic neurotransmission: effects of citalopram.

Deficits in serotonergic (5-HT-ergic) neurotransmission and stressful life events have been implicated in affective disorders, and chronic variable stress (CVS) can elicit behavioral changes reminiscent of increased emotionality, anxiety and atypical depression after partial 5-HT depletion. This study examined the effect of chronic citalopram treatment (10 mg/kg daily) on these changes. Parachloroamphetamine (PCA) (2 mg/kg) reduced the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex, increased anxiety in the social interaction test, and increased activity in the open field. CVS reduced social activity in the social interaction test and immobility time in the forced swimming test. Reduction of excrements left during immobilization indicated partial adaptation with the CVS. Specific stressors had different effects on body weight gain, shorter lasting stressors having a smaller effect in general than those that lasted longer. Combination of CVS and PCA increased sucrose intake after two weeks of stress. In addition, combination of the two treatments reduced diving in the forced swimming test. Citalopram prevented the increase in sucrose consumption in the PCA+CVS rats, and in 5-HT-depleted animals blocked the increase in struggling and reduced the number of defecations in the forced swim test. In conclusion, citalopram treatment prevented several effects of either 5-HT depletion or combined PCA+CVS treatment, suggesting that these behavioral changes could be used in studies on the neural mechanisms underlying emotional behavior that may have relevance to the neurobiology of depression.

Rats with persistently low or high exploratory activity: behaviour in tests of anxiety and depression, and extracellular levels of dopamine.

Behaviour in novel environments is influenced by the conflicting motivators fear and curiosity. Because changes in both of these motivational processes are often simultaneously involved in human affective disorders, we have developed the exploration box test which allows separation of animals belonging to clusters with inherent high neophobia/low motivation to explore and low neophobia/high motivation to explore (LE and HE, respectively). In a novel home-cage, no behavioural differences were found between LE- and HE-rats, suggestive that it is not the general locomotor activity but specific features of the exploration box test that bring about the differences. In studies on both Wistar and Sprague-Dawley rats we found that the trait of exploratory activity remains stable over long periods of time and that LE and HE animals display differences in many other behavioural tests related to mood disorders. Namely, LE animals were found to display enhanced anxiety-like behaviour and to be generally less active in the elevated plus-maze, used more passive coping strategies in the forced swimming test, and acquired a more persistent association between neutral and stressful stimuli in fear conditioning test. LE animals consumed more sucrose solution in non-deprived conditions. We also found that both at baseline and in response to d-amphetamine (0.5mg/kg) administration, LE-rats had lower extracellular dopamine levels in striatum but not in nucleus accumbens. In conclusion, LE-rats appear more inhibited in their activity in typical animal tests of anxiety and are more susceptible to acute stressful stimuli.

Tickling-induced 50-kHz ultrasonic vocalization is individually stable and predicts behaviour in tests of anxiety and depression in rats.

Manipulation of juvenile rats in a way that mimics the rough-and-tumble play and resembles tickling elicits 50-kHz ultrasonic vocalizations (USVs) that have been proposed as a measure of positive affect. In the present experiments the stability of the 50-kHz USV response (chirping) over 1.5 months of daily manipulation and the effect of tickling was studied. By the second week of tickling rats of both sexes developed a level of 50-kHz USVs that remained individually characteristic. During tickling the rats also emitted low levels of 22-kHz USVs. No correlation was found between the two types of USVs. In tests used in anxiety and depression research, tickling on its own had an anxiolytic effect in many experimental settings. Significantly lower levels of [(35)S]GTPgammaS binding to the dopamine-activated receptor-G protein complex in striatum and serotonin transporter levels in the frontal cortex were found in female control rats as compared to males. These differences were eliminated by tickling. Rats which expressed high level of chirping (HC-rats) were similar to low-chirping (LC) rats in anxiety measures but had lower activity in an exploration test and lower sucrose preference. LC-rats adopted more active coping strategies in the forced swimming test. These findings suggest that there are individually characteristic 50-kHz USV response levels to tickling in rats, and that HC- and LC-rats are similar with regard to anxiety levels but have different coping strategies to novelty. The anxiolytic-like changes in behaviour that were brought about by tickling could be mediated by changes in dopamine- and serotonergic systems.

Effect of long-term blockade of CRF(1) receptors on exploratory behaviour, monoamines and transcription factor AP-2.

Corticotropin-releasing factor (CRF) holds a central role in reactions to various environmental stimuli. In the present study, the administration of a selective nonpeptide CRF(1) receptor antagonist, CP-154,526, for 6 days, exerted an anxiolytic effect in the elevated zero-maze (EZM) test. CP-154,526 did not affect behaviour in the exploration box when administered acutely, but increased exploration when administered for 5 days, contingently with daily behavioural testing. This effect, although of lesser magnitude, was also present in animals with neurotoxin DSP-4-induced selective denervation of locus coeruleus (LC) projections. When drug administration and behavioural testing were noncontingent in a 2-week administration schedule, CP-154,526 blocked the habituation-induced increase in exploration. This suggests that drug-environment interaction is an important component in the manifestation of the anxiolytic-like effects of CRF(1) receptor blockade. Long-term administration of CP-154,526 had a decreasing effect on noradrenaline (NA) metabolism in the frontal cortex. No manipulation influenced the levels of the transcription factor AP-2 isoforms in the LC area. AP-2 levels correlated positively with 3-methoxy-4-hydroxyphenylglycol (MHPG) in the frontal cortex of vehicle-treated animals. There was a negative correlation between the NA levels in the hippocampus and AP-2 isoforms in the LC area of naive animals. In contrast, in vehicle-treated animals, this correlation was positive. Treatment with CP-154,526, however, made the associations between LC AP-2 levels and hippocampal NA content negative, as was the case in the naive animals. This suggests that CRF(1) receptor blockade counteracts certain mechanisms of habituation, possibly by reducing the LC activity.

Electrophysiological evidence for change detection in speech sound patterns by anesthetized rats.

Human infants are able to detect changes in grammatical rules in a speech sound stream. Here, we tested whether rats have a comparable ability by using an electrophysiological measure that has been shown to reflect higher order auditory cognition even before it becomes manifested in behavioral level. Urethane-anesthetized rats were presented with a stream of sequences consisting of three pseudowords carried out at a fast pace. Frequently presented "standard" sequences had 16 variants which all had the same structure. They were occasionally replaced by acoustically novel "deviant" sequences of two different types: structurally consistent and inconsistent sequences. Two stimulus conditions were presented for separate animal groups. In one stimulus condition, the standard and the pattern-obeying deviant sequences had an AAB structure, while the pattern-violating deviant sequences had an ABB structure. In the other stimulus condition, these assignments were reversed. During the stimulus presentation, local-field potentials were recorded from the dura, above the auditory cortex. Two temporally separate differential brain responses to the deviant sequences reflected the detection of the deviant speech sound sequences. The first response was elicited by both types of deviant sequences and reflected most probably their acoustical novelty. The second response was elicited specifically by the structurally inconsistent deviant sequences (pattern-violating deviant sequences), suggesting that rats were able to detect changes in the pattern of three-syllabic speech sound sequence (i.e., location of the reduplication of an element in the sequence). Since all the deviant sound sequences were constructed of novel items, our findings indicate that, similarly to the human brain, the rat brain has the ability to automatically generalize extracted structural information to new items.

Revealing the cerebral regions and networks mediating vulnerability to depression: oxidative metabolism mapping of rat brain.

The large variety of available animal models has revealed much on the neurobiology of depression, but each model appears as specific to a significant extent, and distinction between stress response, pathogenesis of depression and underlying vulnerability is difficult to make. Evidence from epidemiological studies suggests that depression occurs in biologically predisposed subjects under impact of adverse life events. We applied the diathesis-stress concept to reveal brain regions and functional networks that mediate vulnerability to depression and response to chronic stress by collapsing data on cerebral long term neuronal activity as measured by cytochrome c oxidase histochemistry in distinct animal models. Rats were rendered vulnerable to depression either by partial serotonergic lesion or by maternal deprivation, or selected for a vulnerable phenotype (low positive affect, low novelty-related activity or high hedonic response). Environmental adversity was brought about by applying chronic variable stress or chronic social defeat. Several brain regions, most significantly median raphe, habenula, retrosplenial cortex and reticular thalamus, were universally implicated in long-term metabolic stress response, vulnerability to depression, or both. Vulnerability was associated with higher oxidative metabolism levels as compared to resilience to chronic stress. Chronic stress, in contrast, had three distinct patterns of effect on oxidative metabolism in vulnerable vs. resilient animals. In general, associations between regional activities in several brain circuits were strongest in vulnerable animals, and chronic stress disrupted this interrelatedness. These findings highlight networks that underlie resilience to stress, and the distinct response to stress that occurs in vulnerable subjects.

Mismatch brain response to speech sound changes in rats.

Understanding speech is based on neural representations of individual speech sounds. In humans, such representations are capable of supporting an automatic and memory-based mechanism for auditory change detection, as reflected by the mismatch negativity (MMN) of event-related potentials. There are also findings of neural representations of speech sounds in animals, but it is not known whether these representations can support the change detection mechanism analogous to that underlying the MMN in humans. To this end, we presented synthesized spoken syllables to urethane-anesthetized rats while local field potentials were epidurally recorded above their primary auditory cortex. In an oddball condition, a deviant stimulus /ga/ or /ba/ (probability 1:12 for each) was rarely and randomly interspersed between frequently presented standard stimulus /da/ (probability 10:12). In an equiprobable condition, 12 syllables, including /da/, /ga/, and /ba/, were presented in a random order (probability 1:12 for each). We found evoked responses of higher amplitude to the deviant /ba/, albeit not to /ga/, relative to the standard /da/ in the oddball condition. Furthermore, the responses to /ba/ were higher in amplitude in the oddball condition than in the equiprobable condition. The findings suggest that anesthetized rat's brain can form representations of human speech sounds, and that these representations can support the memory-based change detection mechanism analogous to that underlying the MMN in humans. Our findings show a striking parallel in speech processing between humans and rodents and may thus pave the way for feasible animal models of memory-based change detection.