In vivo stimulation of locus coeruleus: effects on amygdala subnuclei.

The locus coeruleus (LC) is the major noradrenergic nucleus and sends projections to almost all brain areas. A marked increase in norepinephrine release has been demonstrated in several brain areas in response to exposure to acute stressful stimuli, especially those innervated by LC projections. One of the brain areas innervated by LC neurons is the amygdala, a structure highly involved in emotional processes and memory formation. The aim of this study was to increase knowledge of the functional connectivity between the LC and the amygdala subnuclei. To reach this objective, we evaluated c-fos immunoreactive cells in amygdala nuclei following direct electrical stimulation of the LC in conscious animals. This analysis of c-Fos immunoreactivity could inform whether there are differences in activity of the amygdala subnuclei related to LC electrical stimulation in conscious animals. Our results showed a marked increase in c-fos activity in these amygdala subnuclei both ipsilateral and contralateral to LC electrical stimulation in vivo. Therefore, our study provides evidence that in vivo electrical stimulation of LC is able to activate the amygdala subnuclei as measured by c-fos expression.

Medullary Norepinephrine Projections Release Norepinephrine into the Contralateral Bed Nucleus of the Stria Terminalis.

Central norepinephrine signaling influences a wide range of behavioral and physiological processes, and the ventral bed nucleus of the stria terminalis (vBNST) receives some of the densest norepinephrine innervation in the brain. Previous work describes norepinephrine neurons as projecting primarily unilaterally; however, recent evidence for cross-hemispheric catecholamine signaling challenges this idea. Here, we use fast-scan cyclic voltammetry and retrograde tracing to characterize cross-hemispheric norepinephrine signaling in the vBNST. We delivered stimulations to noradrenergic pathways originating in the A1/A2 and locus coeruleus and found hemispherically equivalent norepinephrine release in the vBNST regardless of stimulated hemisphere. Unilateral retrograde tracing revealed that medullary, but not locus coeruleus norepinephrine neurons send cross-hemispheric projections to the vBNST. Further characterization with pharmacological lesions revealed that stimulations of the locus coeruleus and its axon bundles likely elicit vBNST norepinephrine release through indirect activation. These experiments are the first to demonstrate contralateral norepinephrine release and establish that medullary, but not coerulean neurons are responsible for norepinephrine release in the vBNST.

Locus Coeruleus and Tuberomammillary Nuclei Ablations Attenuate Hypocretin/Orexin Antagonist-Mediated REM Sleep.

Hypocretin 1 and 2 (Hcrts; also known as orexin A and B), excitatory neuropeptides synthesized in cells located in the tuberal hypothalamus, play a central role in the control of arousal. Hcrt inputs to the locus coeruleus norepinephrine (LC NE) system and the posterior hypothalamic histaminergic tuberomammillary nuclei (TMN HA) are important efferent pathways for Hcrt-induced wakefulness. The LC expresses Hcrt receptor 1 (HcrtR1), whereas HcrtR2 is found in the TMN. Although the dual Hcrt/orexin receptor antagonist almorexant (ALM) decreases wakefulness and increases NREM and REM sleep time, the neural circuitry that mediates these effects is currently unknown. To test the hypothesis that ALM induces sleep by selectively disfacilitating subcortical wake-promoting populations, we ablated LC NE neurons (LCx) or TMN HA neurons (TMNx) in rats using cell-type-specific saporin conjugates and evaluated sleep/wake following treatment with ALM and the GABAA receptor modulator zolpidem (ZOL). Both LCx and TMNx attenuated the promotion of REM sleep by ALM without affecting ALM-mediated increases in NREM sleep. Thus, eliminating either HcrtR1 signaling in the LC or HcrtR2 signaling in the TMN yields similar effects on ALM-induced REM sleep without affecting NREM sleep time. In contrast, neither lesion altered ZOL efficacy on any measure of sleep-wake regulation. These results contrast with those of a previous study in which ablation of basal forebrain cholinergic neurons attenuated ALM-induced increases in NREM sleep time without affecting REM sleep, indicating that Hcrt neurotransmission influences distinct aspects of NREM and REM sleep at different locations in the sleep-wake regulatory network.

Locus ceruleus neurons in people with autism contain no histochemically-detectable mercury.

Exposure to environmental mercury has been proposed to play a part in autism. Mercury is selectively taken up by the human locus ceruleus, a region of the brain that has been implicated in autism. We therefore looked for the presence of mercury in the locus ceruleus of people who had autism, using the histochemical technique of autometallography which can detect nanogram amounts of mercury in tissues. In addition, we sought evidence of damage to locus ceruleus neurons in autism by immunostaining for hyperphosphorylated tau. No mercury was found in any neurons of the locus ceruleus of 6 individuals with autism (5 male, 1 female, age range 16-48 years). Mercury was present in locus ceruleus neurons in 7 of 11 (64%) age-matched control individuals who did not have autism, which is significantly more than in individuals with autism. No increase in numbers of locus ceruleus neurons containing hyperphosphorylated tau was detected in people with autism. In conclusion, most people with autism have not been exposed early in life to quantities of mercury large enough to be found later in adult locus ceruleus neurons. Human locus ceruleus neurons are sensitive indicators of mercury exposure, and mercury appears to remain in these neurons indefinitely, so these findings do not support the hypothesis that mercury neurotoxicity plays a role in autism.

Lesion of the locus coeruleus aggravates dopaminergic neuron degeneration by modulating microglial function in mouse models of Parkinson׳s disease.

The degeneration of noradrenergic neurons in the locus coeruleus (LC) commonly occurs in patients with Parkinson's disease (PD), which is characterized by a selective injury of dopaminergic neurons in the substantia nigra (SN). The pathological impact of the LC on the SN in the disease is unknown. In the present study, we used a noradrenergic toxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), to deplete noradrenaline (NA) derived from the LC to explore its influence on degeneration or injury of dopaminergic neurons in the SN in mouse model produced by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or lipopolysaccharide (LPS). Our results demonstrated that lesion of the LC could change microglial function in the brain, which led to enhanced or prolonged expression of pro-inflammatory cytokines, diminished neurotrophic factors, and weakened ability of anti-oxidation in the SN. The in vitro experiments further confirmed that NA could reduce the inflammatory reaction of microglia. The selective injury of dopaminergic neurons by inflammation, however, was due to the inflammation in different brain regions rather than the depletion of NA. Our results indicate that the lesion in the LC is an important factor in promoting dopaminergic neuron degeneration by impacting the function of microglia in the midbrain.

Dorsal subcoeruleus nucleus (SubCD) involvement in context-associated fear memory consolidation.

The neurobiological mechanisms of emotional memory processing can be investigated using classical fear conditioning as a model system, and evidence from multiple lines of research suggests that sleep influences consolidation of emotional memory. In rodents, some of this evidence comes from a common finding that sleep deprivation from 0 to 6 h after fear conditioning training impairs processing of conditioned fear memory. Here, we show that during a 6-h session of sleep-wake (S-W) recording, immediately after a session of context-associated fear conditioning training, rats spent more time in wakefulness (W) and less time in slow-wave sleep (SWS) and rapid eye movement (REM) sleep. This context-associated fear conditioning training-induced reduction in SWS lasts for 2 h, and the REM sleep reduction lasts throughout the entire 6-h post-training S-W recording period. Interestingly, these reductions in SWS and REM sleep during this 6-h period did not impair memory consolidation for context-associated fear conditioning. The results of this study show, for the first time, that lesions within the dorsal part of the subcoeruleus nucleus (SubCD), which were unintentionally caused by the implantation of bipolar recording electrodes, impair consolidation of context-associated fear conditioning memory. Together, the results of these experiments suggest that emotional memory processing associated with fear conditioning can be completed successfully within less than a normal amount of sleep, but it requires a structurally and functionally intact SubCD, an area in the brain stem where phasic pontine wave (P-wave) generating cells are located.

Vagus nerve stimulation enhances perforant path-CA3 synaptic transmission via the activation of ß-adrenergic receptors and the locus coeruleus.

Vagus nerve stimulation (VNS) is an approved treatment for epilepsy and depression and has cognition-enhancing effects in patients with Alzheimer's disease. The hippocampus is widely recognized to be related to epilepsy, depression, and Alzheimer's disease. One possible mechanism of VNS involves its effect on the hippocampus; i.e. it increases the release of noradrenaline in the hippocampus. However, the effect of VNS on synaptic transmission in the hippocampus is unknown. To determine whether VNS modulates neurotransmission in the hippocampus, we examined the effects of VNS on perforant path (PP)-CA3 synaptic transmission electrophysiologically in anaesthetized rats. VNS induces a persistent enhancement of PP-CA3 field excitatory post-synaptic potentials (fEPSPs). Arc, an immediate early gene, was used to identify active brain regions after VNS. The locus coeruleus (LC), which contains the perikarya of noradrenergic projections, harboured more Arc-positive cells, as measured by in-situ hybridization, after 10-min VNS. In addition, electrical lesions of LC neurons or intraventricular administration of the ß-adrenergic receptor antagonist timolol prevented the enhancement of PP-CA3 responses by VNS. In conclusion, the protracted increase in PP-CA3 synaptic transmission that is induced by VNS entails activation of the LC and ß-adrenergic receptors. Our novel findings suggest that information from the periphery modulates synaptic transmission in the CA3 region of the hippocampus.

Role of neurokinin-1 expressing neurons in the locus coeruleus on ventilatory and cardiovascular responses to hypercapnia.

We assessed the role of NK-1 receptors (NK1R) expressing neurons in the locus coeruleus (LC) on cardiorespiratory responses to hypercapnia. To this end, we injected substance P-saporin conjugate (SP-SAP) to kill NK-1 immunoreactive (NK1R-ir) neurons or SAP alone as a control. Immunohistochemistry for NK1R, tyrosine hydroxylase (TH-ir) and Glutamic Acid Decarboxylase (GAD-ir) were performed to verify if NK1R-expressing neurons, catecholaminergic and/or GABAergic neurons were eliminated. A reduced NK1R-ir in the LC (72%) showed the effectiveness of the lesion. SP-SAP lesion also caused a reduction of TH-ir (66%) and GABAergic neurons (70%). LC SP-SAP lesion decreased by 30% the ventilatory response to 7% CO(2) and increased the heart rate (fH) during hypercapnia but did not affect MAP. The present data suggest that different populations of neurons (noradrenergic, GABAergic, and possibly others) in the LC express NK1R modulating differentially the hypercapnic ventilatory response, since catecholaminergic neurons are excitatory and GABAergic ones are inhibitory. Additionally, NK1R-ir neurons in the LC, probably GABAergic ones, seem to modulate fH during CO(2) exposure, once our previous data demonstrated that catecholaminergic lesion does not affect this variable.

Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function.

The present studies examined the role of norepinephrine (NE) system in mediating the enhancement of 5-HT function produced by neurokinin (NK)1 receptor antagonism. Dorsal raphe 5-HT and locus coeruleus NE neurons were recorded in vivo in mice lacking NK1 receptors in wildtype mice pretreated with the NK1 antagonist RP67580 and its inactive enantiomer RP 68651. RP67580 and RP68651 were also tested on 5-HT neurons of mice lacking the 5-HT(1A) receptor. RP67580 increased the firing rate of 5-HT neurons in wildtype mice and in 5-HT(1A) null mutant mice to the same degree, thus indicating that the mechanism by which NK1 antagonists enhances 5-HT firing is independent of 5-HT(1A) receptors. NE neuronal burst activity was increased in NK1 null mutant and wildtype mice given RP67580, but not with RP68651. After NE depletion, RP67580 was ineffective in increasing 5-HT neuronal firing activity in NK1 wildtype mice, and the enhancement of 5-HT neuronal firing observed in NK1 null mutant mice was abolished. In conclusion, NE neurons are essential for the action of NK1 antagonists on 5-HT neurons. In addition, the desensitization of 5-HT(1A) autoreceptors produced by NK1 receptor antagonism is not critical for enhancing 5-HT neuronal firing.

Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer's disease.

Loss of Locus coeruleus (LC) noradrenergic (NA) neurons occurs in several neurodegenerative conditions including Alzheimer's disease (AD). In vitro and in vivo studies have shown that NA influences several features of AD disease including inflammation, neurodegeneration, and cognitive function. In the current study we tested if LC loss influenced beta amyloid (Abeta) plaque deposition. LC neuronal degeneration was induced in transgenic mice expressing mutant V717F human amyloid precursor protein (APP) by treatment with the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine DSP4 (5mg/kg every 2 weeks beginning at age 3 months). At 9 months of age, when control mice show low amyloid load, DSP4-treated mice showed an approximately 5-fold increase in the average number of Abeta plaques. This was accompanied by an increase in the levels of APP C-terminal cleavage fragments. DSP4-treatment increased both microglial and astroglial activation. In vivo, DSP4-treatment decreased expression and activity of the Abeta degrading enzyme neprilysin, while in vitro NA increased phagocytosis of Abeta1-42 by microglia. These findings suggest that noradrenergic innervation from LC are needed to maintain adequate Abeta clearance, and therefore that LC degeneration could contribute to AD pathogenesis.

Effects of clonidine in the locus coeruleus on prefrontal- and hippocampal-dependent measures of attention and memory in the rat.

RATIONALE: The locus coeruleus (LC) is the source of norepinephrine (NE) in the prefrontal cortex (PFC) and hippocampus and may influence cognitive functions of these areas. Chronic effects of LC-NE lesions do not correspond consistently with acute effects of systemic or intracortical injections of adrenergic agents. OBJECTIVE: These studies aim to manipulate LC activity pharmacologically and study acute effects on measures of attention and memory that depend on the PFC and hippocampus. METHODS: Rats were trained to criterion for one of three tasks: visuospatial reaction time (VSRT), a measure of attention sensitive to PFC lesions, delayed matching trained with retractable levers (DM-RL), and delayed nonmatching trained in radial mazes (DNM-RM), measures of spatial working memory sensitive to PFC and hippocampal lesions, respectively. LC activity was manipulated with bilateral 0.5-microl injections of the alpha-2 agonist clonidine (0, 1.1, 4.5, and 18 nmol). RESULTS: Clonidine produced significant dose-dependent impairments of VSRT, affecting choice response time at the 18-nmol dose and choice accuracy at the 4.5- and 18-nmol doses. Clonidine had no effect on DMRL or DNM-RM at any of the doses tested. CONCLUSIONS: Reversible reduction of LC-NE activity by clonidine impaired measures of visuospatial attention sensitive to PFC lesions but were insufficient to affect PFC- or hippocampal-dependent measures of spatial working memory. These results are consistent with reports that LC-NE lesions produce chronic deficits in attention with little or no effect on measures of working memory.

Role of the locus coeruleus in the prolactin secretion of female rats.

Since locus coeruleus (LC) lesion blocks preovulatory prolactin surge, the aim of this study was to determine if this lesion would also block prolactin surges induced by steroids in ovariectomized rats and would modify basal prolactin secretion. To determine the time of the steroid-induced prolactin surges, ovariectomized rats treated with estradiol (OVE) or estradiol and progesterone (OVEP) were cannulated at 08:00 h and blood samples were collected hourly between 14:00 and 18:00 h. Ovariectomized rats treated with oil (OV-Oil) were used as control. Prolactin peaked at 16:00 h in OVE rats and at 15:00 h in OVEP. In a second experiment, male rats, cycling rats, OVE, OVEP, and OV-Oil groups were cannulated at 08:00 h, followed by LC lesion or sham-surgery. Blood samples were withdrawn at times of basal and peak prolactin levels. LC lesion blocked afternoon prolactin surges of OVE, OVEP and proestrus rats. However, the low levels observed at 16:00 h in OV-Oil, diestrus and male rats as well as at 11:00 h in OVE, OVEP, estrus, and proestrus rats were not modified by LC lesion. The high prolactin levels observed on estrus afternoon were dramatically reduced by LC lesion. Data suggest that LC neurons are important for steroid-induced prolactin surge genesis, but not for prolactin basal secretion.

A damage to locus coeruleus neurons converts sporadic seizures into self-sustaining limbic status epilepticus.

Various studies demonstrated that the neurotransmitter norepinephrine (NE) plays a relevant role in modulating seizures; in particular, a powerful effect consists in delaying the kindling of limbic areas such as the amygdala and hippocampus. Given the rich NE innervation of limbic regions, we selected a sensitive trigger area, the anterior piriform cortex, to test whether previous loss of noradrenergic terminals modifies sporadic seizures in rats. The damage to locus coeruleus terminals was produced by using the selective neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 60 mg/kg i.p.). In intact rats, bicuculline (a GABA-A antagonist, 118 pmol) microinfused into this area produced sporadic seizures, while in rats previously injected with DSP-4, bicuculline determined long-lasting self-sustaining status epilepticus. In intact rats, sporadic seizures were accompanied by a marked increase in norepinephrine release in the contralateral piriform cortex, while in locus coeruleus-lesioned rats this phenomenon was attenuated. While bicuculline-induced sporadic seizures were prevented by the focal infusion of amino-7-phosphonoheptanoic acid (AP-7, a selective NMDA antagonist), or 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulphonamide (NBQX, a selective non-NMDA antagonist), status epilepticus obtained in norepinephrine-lesioned rats was insensitive to AP-7 but was still inhibited by NBQX. By using fluorescent staining for damaged (Fluoro-Jade B) and intact (DAPI) neurons, as well as cresyl violet, we found that rats undergoing status epilepticus developed neuronal loss in various limbic regions. This study demonstrates a powerful effect of noradrenergic terminals in regulating the onset of limbic status epilepticus and its sensitivity to specific glutamate antagonists.

Coeruleotrigeminal suppression of nociceptive sensorimotor function during inflammation in the craniofacial region of the rat.

Descending action from the locus coeruleus (LC) on the trigeminal sensorimotor function was evaluated in a rat model of oral-facial inflammation. For the induction of oral-facial inflammation, mustard oil (20% solution in 20microl mineral oil) was injected into the region of the temporomandibular joint (TMJ). One week before testing, rats received bilateral lesions of the LC using a cathodal current. The electromyogram (EMG) threshold, which is the threshold intensity for the onset of EMG activity of the masseter muscle evoked by pressure on the TMJ region, was used in the present study as an indicator of the trigeminal sensorimotor function. Following mustard oil injection, in the LC-lesioned rats, EMG thresholds significantly decreased at 30min, which lasted up to 240min. In contrast, EMG thresholds in the LC-intact rats returned to the level before injection after 180min. Systemic naloxone (1.3mg/kg, i.v.) produced a further decrease of EMG thresholds in both the LC-intact and LC-lesioned rats. Under the existence of naloxone, EMG thresholds in the LC-lesioned rats were significantly lower than those of the LC-intact rats. These results suggest that oral-facial inflammation activates the coeruleotrigeminal modulating system and that an action of this system is independent of the opioid depressive mechanism.

[Bilateral lesion of locus coeruleus in rats induces haemorrhage in multiple visceral organs].

AIM AND METHODS: The haemorrhagic changes of the urinary bladder, as well as that of other visceral organs, were checked histologically in rats being received bilateral electrolytic lesion of the locus coeruleus (LC). RESULTS: Complete lesion of bilateral LC constantly induced severe haemorrhage of the urinary bladder, accompanied with blood congestion or slight haemorrhage of other visceral organs. Partial lesion of bilateral LC also induced blood congestion or slight haemorrhage in multiple visceral organs, but the urinary bladder did not show haemorrhage change. Reduction of stress by adrenalectomy before lesion of the LC, or administration of antagonist of histamine H2 receptor, had no obvious effect on the haemorrhage of the urinary bladder and histological changes of other visceral organs. CONCLUSION: These results indicate that the haemorrhagic change of multiple visceral organs induced by bilateral lesion of the LC in rats is not due to stress, or due to involvement of histamine H2 receptor. The mechanism needs to be studied further.

Light-induced zif268 expression is dependent on noradrenergic input in rat visual cortex.

In the present paper we investigated the role of the noradrenergic projection from the locus coeruleus on the expression of the immediate early gene zif268 in the visual cortex of rats exposed to ambient light stimulation. Local administrations of 6-hydroxydopamine (6-OHDA), a specific toxin directed against the catecholaminergic system, were performed in the locus coeruleus prior to visual stimulation. Animals were stimulated for 2 h by ambient light, after a 2-week dark adaptation period. Sham-operated controls displayed a massive increase in the number of zif268 positive cells after light stimulation. To the contrary, lesioned animals demonstrated a dramatic reduction in the number of zif268 positive nuclei across all cortical layers. A few scattered immunopositive nuclei were identified in cortical layer IV, however, this region also underwent a significant reduction in the number of zif268 immunopositive nuclei. Our results indicate that the noradrenergic system plays an important role in the expression of zif268 in the visual cortex of rats exposed to ambient light after dark isolation.

Dose-dependent effects of noradrenergic denervation by DSP-4 treatment on forced swimming and beta-adrenoceptor binding in the rat.

DSP-4 is a neurotoxin highly selective for the noradrenergic nerve terminals originating from the locus coeruleus. Preliminary data suggested that its effect in a typical screening test for antidepressant drugs, the forced swimming test, is biphasic dependent on the dose. In the present study, DSP-4 was administered in four doses (5, 10, 30 and 50mg/kg) to male Wistar rats. Administration of the neurotoxin had a dose-dependent biphasic effect on immobility time in the forced swimming test 8 and 9 days later. Thus, DSP-4 at the dose of 10mg/kg increased immobility, but higher doses reduced this measure. The reduction of noradrenaline concentration in the frontal cortex and hippocampus was dose-dependent starting from the dose 10mg/kg. Cortical beta-adrenoceptor binding was increased by DSP-4 treatment at the doses 30mg/kg and 50mg/kg. These results suggest that the increase in immobility time in the forced swimming test is associated with presynaptic changes in noradrenaline availability, whereas the decrease in immobility observed after more complete denervation is associated with postsynaptic receptor supersensitivity.

Vibrissectomy induced changes in GAP-43 immunoreactivity in the adult rat barrel cortex.

Within the rat primary somatosensory cortex, neurons responding principally to movement of each individual mystacial vibrissa are grouped together in structures termed barrels. Previous studies have examined changes in the area of cortex showing increased 2-deoxyglucose uptake in response to vibrissal stimulation. These studies have shown that chronic removal of all but the central (C3) vibrissa in adult rats induces an enlarged representation of the remaining C3 barrel in the contralateral cortex. This increase is prevented by cortical norepinephrine depletion. The major question raised by such studies is whether such plasticity is due to structural rearrangement or unmasking of otherwise silent synapses. In this study, antibodies to GAP-43, a presynaptic protein whose synthesis is related to neuronal development and regeneration, were used to investigate this issue. In adult rat brain, tangential sections through layer IV of the barrel receptor field normally show moderate levels of GAP-43 immunoreactivity (GAP-IR) in the inter-barrel septa and low levels within the barrels themselves. The present study examined changes in the pattern of GAP-IR from 1 to 8 weeks after vibrissectomy with sparing of C3 as an index of possible physical reorganization of cortical circuits. Quantitative analysis of the cortices of animals with unilateral vibrissectomy with sparing of C3 showed that the area of low GAP-IR within the barrels surrounding C3 was decreased at 1 week (8.4% shrinkage; P less than 0.01) and 8 weeks (12.0% shrinkage; P less than 0.015), relative to the cortex ipsilateral to the surgery. Both bilateral vibrissectomy with sparing of C3 and ibotenic acid lesions of the ventrobasal thalamus produced similar results. Some evidence was also seen that the area of low GAP-IR in the C3 barrel shrank to a similar degree after such manipulations. Cortical norepinephrine depletion had no apparent effect on vibrissectomy-induced GAP-IR changes. These results suggest that removal of vibrissal input to the adult rat barrel cortex produces transynaptic induction of axonal sprouting within the barrel cortex.

[The dynamic behavioral changes in rats after destruction of the locus coeruleus]. / Dinamika izmenenii povedeniia krys posle razrusheniia locus coeruleus.

Destruction of locus coeruleus (LC) was conducted in adult rats (male rats of the Wistar line, 250-300 g) electrolytically or by means of 6-hydroxydopamine (6-OHDA). Behaviour of the intact animals sham-operated and of rats with destructed LC was evaluated before and every week after the operation during 5 weeks. Statistically significant alterations in the behaviour were revealed only in the initially low-active rats. These animals were characterized firstly, by low motor and exploratory activity in all tests (open field and automated devices), disturbance of the reactivity to novelty--only in one week after the operation with subsequent compensation of shifts; secondly, by low level of investigatory activity in the open field and absence of habituation to the repetitive tests--from the 21-st day after the operation.