Region-specific dysregulation of allopregnanolone brain content in the olfactory bulbectomized rat model of depression

Allopregnanolone (ALLO) is one of the most potent positive endogenous allosteric modulators of the type A γ-aminobutyric acid (GABA_A) receptors. While the robust anxiolytic profile of ALLO has been extensively characterized in rodents and its antidepressant-like effect was recently demonstrated in mice, there have been only few reports on alterations of brain ALLO levels in putative animal models of depression and anxiety. Removal of the olfactory bulbs of rats produces one of the most predictive animal models with which to screen for drugs with potential antidepressant activity following repeated treatment. We therefore investigated whether the olfactory bulbectomized (OB) rat model of depression may be associated with alterations of ALLO levels in whole brain tissue and in different brain regions. We determined ALLO levels in whole brain, amygdala, frontal cortex, hippocampus, and whole cerebral cortex of OB or sham-operated rats at 7, 14, or 28 days following bulbectomy or sham surgery. We observed a significant increase of whole brain ALLO content at 7 and 28 days post-surgery in the OB rats. At days 7 and 14 following olfactory bulb removal, ALLO levels were significantly decreased in amygdala and frontal cortex and significantly increased in whole cerebral cortex. In the hippocampus we observed only a tendency for decreased ALLO levels at day 14. Our data indicates a strong region-specific dysregulation of ALLO homeostasis in brains of OB rats which may contribute to the formation of the bulbectomy syndrome via a sustained reduction in physiological GABA-ergic tone in amygdala and frontal cortex.     

Differential effects of olfactory bulbectomy on β-adrenoceptors in rat amygdala, hippocampus and cerebral cortex

Rats were bilaterally olfactory bulbectomized. At 15 days post-lesion, olfactory bulbectomized (OB) rats exhibited significant deficits in the acquisition of passive avoidance learning compared to sham lesioned rats. β-Adrenoceptor binding in the amygdala, hippocampus and cerebral cortex was assayed with (−)-[¹²⁵I]iodocyanopindolol (ICYP). Scatchard analyses revealed no difference between OB and sham rats in maximal binding density (B_max) in any of the three tissues. However, inthe OB rats, the affinity of the β-adrenoceptor for the ligand was significantly increased in the amygdala and hippocampus but not in the cortex. Bulbectomy did not affect the ratio ofβ₁- toβ₂-adrenoceptor subtypes in the three brain tissues. In amygdala and hippocampus but not cerebral cortex, bulbectomy resulted in an increase in the proportion and the affinity of the high-affinity β-adrenoceptor binding sites for isoproterenol. The affinity of the low-affinity sites in the hippocampus was also increased in the OB rats. The results suggest that olfactory bulbectomy causes supersensitivity of the amygdaloid and hippocampal β-adrenoceptor by increasing the degree of coupling of the receptor with the stimulatory guanine nucleotide binding protein (G_s protein).     

Disruption of noradrenergic transmission and the behavioural response to a novel environment in NK1R-/- mice

The behaviour of neurokinin-1-receptor gene knockout (NK1R-/-) mice, which lack functional, substance P-preferring receptors, resembles that of NK1R+/+ mice treated with an antidepressant. Because all antidepressants increase central monoamine transmission, we have investigated whether noradrenergic transmission is increased in NK1R-/- mice and, if so, whether this could influence their behaviour. In anaesthetized subjects, the concentration of extracellular noradrenaline in NK1R-/- mice was two-fourfold greater than in NK1R+/+ mice. Systemic administration of the alpha2-adrenoceptor antagonist, 2-(2,3-dihydro-2-methoxy-1,4-benzodioxan-2-yl)-4,5-dihydro-1H-imidazoline (RX 821002), in anaesthetized or freely moving animals increased extracellular noradrenaline in NK1R+/+ mice only. This suggests that the function of alpha2a-autoreceptors, which modulate noradrenergic transmission, is impaired in NK1R-/- mice. Consistent with this, [35S]GTPgammaS binding to activated alpha2a-adrenoceptors was lower (-70%) in the locus coeruleus, but not the frontal cortex, of NK1R-/- mice compared with their NK1R+/+ counterparts. RX 821002-pretreatment, followed by retrodialysis of the noradrenaline reuptake inhibitor, desipramine, into the frontal cortex of anaesthetized mice increased extracellular noradrenaline to the same extent in the two genotypes. Western blots confirmed that there was no difference in the amount of noradrenaline transporter protein in NK1R-/- and NK1R+/+ mice. Finally, the effects of RX 821002 on certain behaviours in a light/dark exploration box were blunted in NK1R-/- mice, but there was no consistent effect on anxiety-like behaviour in the two genotypes. It is concluded that the greater basal efflux of noradrenaline in NK1R-/- mice is explained by increased transmitter release, coupled with desensitization of somatodendritic alpha2a-adrenoceptors. These changes could contribute to the difference in the behavioural phenotypes.     

Stress-resistant mice overexpressing glucocorticoid receptors display enhanced BDNF in the amygdala and hippocampus with unchanged NGF and serotonergic function

Dysfunctional glucocorticoid receptor (GR) signaling has been shown to be involved in the pathogenesis of depressive behavior in mice and humans. In accordance with this hypothesis GR overexpressing mice are less susceptible to develop depressive-like behavior when subjected to stressful events. Here, we analyzed GR overexpressing mice for morning and evening content of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and the tissue levels of serotonin and its metabolite 5-hydroxyindoleacetic acid) in brain areas suspected to be involved in stress adaptation. BDNF concentrations in the hippocampus and amygdala/piriform cortex were significantly enhanced in GR overexpressing mice (by maximally +103%) compared to wildtype animals. Diurnal variations, as detected for NGF in the hypothalamus, for BDNF in the frontal cortex and striatum and for serotonergic function in the frontal cortex and hypothalamus, were not affected by the genotype. In conclusion, GR overexpression-dependent increases of hippocampal and amygdala BDNF content presumably represent a dynamic correlate of enhanced stress resistance.     

Increased BDNF and trk-B mRNA expression in cortical and limbic regions following formation of a social recognition memory

Brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine receptor kinase (trk-B), play important roles in neural plasticity, long-term potentiation and memory formation. Sheep form a selective recognition memory for their lambs within 2 h of birth. Initially, this memory is exclusively based on olfactory cues; however, as it consolidates over a 12-h recognition period it extends to incorporate visual cues. We investigated whether changes in BDNF and trk-B mRNA expression occurred in both olfactory and visual processing systems at 4.5 h postpartum, 2-3 h after the behavioural manifestations of an olfactory recognition memory were found. Animals that formed a recognition memory showed increased BDNF mRNA expression in the inferior part of the temporal cortex, subfield CA1 of the hippocampus, the diagonal band, basolateral amygdala and the anterior cingulate, medial frontal, entorhinal and pyriform cortices. No increases were observed in either the olfactory bulbs or the dentate gyrus. Expression of trk-B mRNA was significantly increased only in the medial temporal, entorhinal and pyriform cortices. These findings demonstrate that by 2-3 h following the initial formation of olfactory recognition memory there are BDNF/trk-B-mediated plasticity changes in brain areas involved in the consolidation of olfactory memory (the pyriform and entorhinal cortices). However, similar changes also occur in areas of the brain involved in visual memory, face and object recognition (the temporal cortex, entorhinal cortex, hippocampal subfield CA1 and basolateral amygdala), and in areas of the brain with integrative and attentional functions (the medial frontal and anterior cingulate cortices and diagonal band). This suggests that reorganization of neural circuits underlying the visual recognition of lambs or the integration of olfactory/visual information is occurring even at this time even though accurate behavioural recognition at this stage can only be made using olfactory cues.     

Cellular localization of serotonin(2A) (5HT(2A)) receptors in the rat brain

The serotonin(2A) (5HT(2A)) receptors have been shown to play an important role in several psychiatric disorders, including depression, schizophrenia, and alcoholism. This immunohistochemical study examined the cellular localization of 5HT(2A) receptors in various rat brain structures (olfactory, striatum, cortex, hippocampus, and amygdala). The colocalization of 5HT(2A) receptors in astrocytes was performed by double-immunofluorescence staining of 5HT(2A) receptors and of glial fibrillary acidic protein (GFAP) using confocal laser microscopy. 5HT(2A) receptor immunolabeling was observed in olfactory bulbs, neostriatum, hippocampus, amygdala, and neocortex. Somata and dendrites of pyramidal cells in the frontal cortex (layer V) were densely labeled with 5HT(2A) receptors. In several other brain structures (hippocampus, amygdala, striatum, olfactory structures), 5HT(2A) receptor immunolabeling was found in cell bodies and processes of neurons. 5HT(2A) receptor immunolabeling was also observed in GFAP-positive cells of the various brain structures we investigated (layers I/VI of the neocortex, corpus callosum, hippocampal fissure and hilus, and amygdala). These results indicate that 5HT(2A) receptors are expressed in neurons and astrocytes and suggest the possibility that not only neuronal but also glial 5HT(2A) receptors have functional implications in psychiatric disorders.     

Regional changes in [3H]diazepam binding in the brains of mice after removal of the olfactory bulbs

[³H]Diazepam binding was assayed 3 weeks after surgery in 13 brain regions derived from sham-operated and bilaterally olfactory bulbectomized mice. In bulbectomized mice, [³H]diazepam binding was elevated 30% in the frontal cortex and 24% in the thalamus but decreased 26% in the striatum and 28% in the midbrain. These changes represented alterations in the number of binding sites. No binding changes were observed in the olfactory tubercle, amygdala, piriform cortex, olfactory peduncle, hypothalamus, hippocampus, colliculi, cerebellum, or pons-medulla of bulbectomized animals. These results are compared with the effects of other types of brain lesions on the brain benzodiazepine receptor, and are possibly related to the altered sensitivity of bulbectomized mice to benzodiazepines and convulsants.     

Cellular localization of serotonin2A (5HT2A) receptors in the rat brain

The serotonin_2A (5HT_2A) receptors have been shown to play an important role in several psychiatric disorders, including depression, schizophrenia, and alcoholism. This immunohistochemical study examined the cellular localization of 5HT_2A receptors in various rat brain structures (olfactory, striatum, cortex, hippocampus, and amygdala). The colocalization of 5HT_2A receptors in astrocytes was performed by double-immunofluorescence staining of 5HT_2A receptors and of glial fibrillary acidic protein (GFAP) using confocal laser microscopy. 5HT_2A receptor immunolabeling was observed in olfactory bulbs, neostriatum, hippocampus, amygdala, and neocortex. Somata and dendrites of pyramidal cells in the frontal cortex (layer V) were densely labeled with 5HT_2A receptors. In several other brain structures (hippocampus, amygdala, striatum, olfactory structures), 5HT_2A receptor immunolabeling was found in cell bodies and processes of neurons. 5HT_2A receptor immunolabeling was also observed in GFAP-positive cells of the various brain structures we investigated (layers I/VI of the neocortex, corpus callosum, hippocampal fissure and hilus, and amygdala). These results indicate that 5HT_2A receptors are expressed in neurons and astrocytes and suggest the possibility that not only neuronal but also glial 5HT_2A receptors have functional implications in psychiatric disorders.     

Neurokinin2-R in medial septum regulate hippocampal and amygdalar ACh release induced by intraseptal application of neurokinins A and B

The neurokinin receptors (NK-R), NK(2)- and NK(3)-R, have been implicated in behavioral processes, but apparently in opposite ways: while NK(2)-R agonism disrupts memory and has anxiogenic-like action, NK(3) -R agonists facilitate memory and display anxiolytic-like effects. Systemic application of NK(2)-R antagonists block the release of acetylcholine (ACh) in the hippocampus, which is induced by intraseptal administration of the NK(2)-R ligand, neurokinin A (NKA). We investigated the effects of medial septal injection of NKA and a preferred ligand of NK(3)-R, neurokinin B (NKB), on the activity of cholinergic neurons of the basal forebrain and assessed the role of the medial septal NK(2)-R in the control of extracellular ACh levels in cholinergic projection areas. ACh was dialysed in the frontal cortex, amygdala and hippocampus of anesthetized animals and was analysed by HPLC-EC. ACh levels in hippocampus and amygdala, but not in frontal cortex were increased after intraseptal injection of either NKA or NKB (0.1, 1, 10 μM). Application of the nonpeptidic NK(2)-R antagonist, saredutant SR48968 (1, 10, 100 pM), followed by NKA (1 μM) or NKB (10 μM) injection into the medial septum, blocked the ACh increase in hippocampus and amygdala. These results indicate that medial septal NK(2)-R have an important role in mediating ACh release, for one, via the septal-hippocampal cholinergic projection and, secondly, via direct or indirect route to the amygdala, but not frontal cortex. They also support the hypothesis that hippocampal cholinergic neurotransmission controls amygdala function suggesting that this interaction is regulated via NK(2)-R in the medial septum.     

Changes in neurotransmitter metabolism following olfactory bulbectomy in the rat

Bilateral ablation of the olfactory bulbs caused marked changes in the 'turnover' of several neurotransmitters in the amygdaloid cortex and the mid-brain areas of the rat brain. Following tyrosine and tryptophan hydroxylase inhibition, the decrease in the concentration of noradrenaline and serotonin respectively in the amygdaloid cortex was not so marked in the bulbectomized rats as in their controls. This suggests that the 'turnover' of these biogenic amines is reduced following bulbectomy. Following GABA transaminase inhibition, the increase in the concentration of GABA in this region was increased compared to the controls thereby suggesting that the 'turnover' of the inhibitory neurotransmitter was enhanced, glutamate decarboxylase activity was also increased in the amygdaloid cortex. No changes were found in the 'turnover' of noradrenaline or serotonin in the mid-brain but that of dopamine was decreased as was the activity of glutamate decarboxylase. It is concluded that changes in neurotransmitter 'turnover' in these brain regions are attributable to the destruction of the olfactory bulbs and may contribute to the behavioural deficits which we, and others, have reported elsewhere.     

Altered host response to murine gammaherpesvirus 68 infection in mice lacking the tachykinin 1 gene and the receptor for substance P

The tachykinins are implicated in neurogenic inflammation and the neuropeptide substance P in particular has been shown to be a proinflammatory mediator. A role for the tachykinins in host response to viral infection has been previously demonstrated using either TAC1- or NK1 receptor-deficient transgenic mice. However, due to redundancy in the peptide-receptor complexes we wished determine whether a deficiency in TAC1 and NK1^R in combination exhibited an enhanced phenotype. TAC1 and NK1^R-deficient mice were therefore crossed to generate transgenic mice in both (NK1^−/− × TAC1^−/−). As expected, after infection with the respiratory pathogen murine gammaherpesvirus (MHV-68), TAC1 and NK1^R-deficient mice were more susceptible to infection than wild-type C57BL/6 controls. However, unexpectedly, NK1^−/− × TAC1^−/− mice were more resistant to infection arguing for a lack of feedback inhibition through alternative receptors in these mice. Histopathological examination did not show any great differences in the inflammatory responses between groups of infected animals, except for the presence of focal perivascular B cell accumulations in lungs of all the knockout mice. These were most pronounced in the NK1^−/− × TAC1^−/− mice. These results confirm an important role for TAC1 and NK1^R in the control of viral infection but reinforce the complex nature of the peptide-receptor interactions.     

The NMDA receptor antagonist MK-801 does not protect against serotonin depletions caused by high doses of DL-fenfluramine.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) has been shown to block methamphetamine (MA) induced damage to the dopamine (DA) and serotonin (5HT) systems of the brain. DL-Fenfluramine (FEN) is another potential neurotoxin but its long-term depletions are more selective to the 5HT system. To determine whether MK-801 protects against damage induced by FEN, we treated rats with FEN (4 injections of 12.5 mg/kg, at 1 h intervals) in conjunction with either saline or MK-801 (2 injections of 2.5 mg/kg, administered 15 min before and 90 min after the first FEN injection). Two weeks post-treatment, MK-801 alone caused a small but significant decrease in 5HT tissue concentrations in striatum and amygdala. FEN significantly reduced 5HT in all 8 brain regions studied. MK-801 + FEN did not protect against FEN-induced 5HT depletions in nucleus accumbens/olfactory tubercle, septum, frontal cortex, somatosensory cortex or hippocampus. MK-801 + FEN enhanced 5HT depletions in striatum, hypothalamus and amygdala. The differential protective effect of MK-801 between MA and FEN are discussed in terms of a possible dopaminergic mechanism.     

Symptom provocation in specific phobia affects the substance P neurokinin-1 receptor system.

BACKGROUND: Animal studies demonstrate that stress and negative affect enhance the release of the neuropeptide substance P (SP), which binds to the neurokinin 1 (NK1) receptor. This positron emission tomography (PET) study evaluated how the activity in the SP-NK1 receptor system in the amygdala was affected by fear provocation in subjects with specific phobia. METHODS: Sixteen adult women with DSM-IV-defined specific phobia for either snakes or spiders but not both viewed pictures of feared and non-feared animals while being PET-scanned for 60 min with the highly specific NK1 receptor antagonist [(11)C]GR205171 as the labeled PET tracer. RESULTS: The uptake of the labeled NK1 receptor antagonist was significantly reduced in the right amygdala during phobic stimulation. In the left amygdala no significant differences were found between phobic and non-phobic conditions. There was a negative correlation in the right, but not left, amygdala between subjective anxiety ratings and NK1 tracer binding. CONCLUSIONS: Fear provocation affects the SP-NK1 receptor system in the right amygdala. This reflects reduced NK1 receptor availability during fear and could mirror an increased release of endogenous substance P.     

Autoradiographic localization of 3H-paroxetine-labeled serotonin uptake sites in rat brain

Paroxetine is a potent and selective inhibitor of serotonin uptake into neurons. Serotonin uptake sites have been identified, localized, and quantified in rat brain by autoradiography with 3H-paroxetine; 3H-paroxetine binding in slide-mounted sections of rat forebrain was of high affinity (KD = 10 pM) and the inhibition affinity constant (Ki) values of various drugs in competing 3H-paroxetine binding significantly correlated with their reported potencies in inhibiting synaptosomal serotonin uptake. Serotonin uptake sites labeled by 3H-paroxetine were highly concentrated in the dorsal and median raphe nuclei, central gray, superficial layer of the superior colliculus, lateral septal nucleus, paraventricular nucleus of the thalamus, and the islands of Calleja. High concentrations of 3H-paroxetine binding sites were found in brainstem areas containing dopamine (substantia nigra and ventral tegmental area) and norepinephrine (locus coeruleus) cell bodies. Moderate concentrations of 3H-paroxetine binding sites were present in laminae I and IV of the frontal parietal cortex, primary olfactory cortex, olfactory tubercle, regions of the basal ganglia, septum, amygdala, thalamus, hypothalamus, hippocampus, and some brainstem areas including the interpeduncular, trigeminal, and parabrachial nuclei. Lower densities of 3H-paroxetine binding sites were found in other regions of the neocortex and very low to nonsignificant levels of binding were present in white matter tracts and in the cerebellum. Lesioning of serotonin neurons with 3,4-methylenedioxyamphetamine caused large decreases in 3H-paroxetine binding. The autoradiographic distribution of 3H-paroxetine binding sites in rat brain corresponds extremely well to the distribution of serotonin terminals and cell bodies as well as with the pharmacological sites of action of serotonin.     

Autoradiographic analyses of 5-HT1A and 5-HT2A receptors after social isolation in mice

Social isolation of rodents is used to model human psychopathological processes. In the present study, the effects of intermediate and long term isolation housing on postsynaptic 5-HT_1A and 5-HT_2A receptors were analyzed in male mice housed in groups or isolation for 4 and 12 weeks. [³H]8-OH-DPAT and [³H]ketanserin were used to label 5-HT_1A and 5-HT_2A receptors. Four representative sagittal sections (planes 1–4) were scored by in vitro autoradiography. Whereas after 4 weeks of housing both receptor densities were lowered significantly in isolated mice, after 12 weeks of housing only marginal isolation effects were seen. Intermediate isolation reduced 5-HT_1A receptors especially in the lateral frontal, parietal and entorhinal cortex (−63%), in the lateral CA1–3 and dentate gyrus region of the hippocampus (−68%), in the basolateral, basomedial, central and medial amygdaloid nuclei (between −38 and −66%), and in the hypothalamus (−28%). 5-HT_2A receptors were strongly reduced in the frontal cortex (between −47 and −74%), in the hippocampus (between −47 and −95%), in the striatum (between −66 and −76%), and in the accumbens nucleus (between −59 and −73%) in comparison to group housed control mice. After 12 weeks of isolation in the hippocampus continuously decreased 5-HT_1A receptor densities were demonstrated (between −24 and −61%). But increased 5-HT_2A receptor densities were seen in the lateral striatum (+86%) compared to control mice. Age-dependent effects were also found. After 12 weeks of group housing the 5-HT_1A and 5-HT_2A receptor densities were decreased (between −28 and −54%) in all analyzed brain regions in comparison to 4 weeks of group housing. Isolated animals showed diminished 5-HT_1A receptor densities in the cortex (−14%) and hippocampus (−15%), but increased 5-HT_1A receptor densities in the amygdala (+33%) after 12 weeks. The 5-HT_2A receptor densities were increased in all analyzed regions (between +31 and +96%) after 12 weeks of isolation compared to 4 weeks. To explain these dynamic, time-dependent pattern of isolation-induced changes different regulation processes are supposed regarding 5-HT_1A and 5-HT_2A receptors. Besides metabolism-related adaptation processes also neurotransmitter and hormonal (e.g., glucocorticoid) interactions especially in limbic regions have to be considered.     

Olfactory projection systems, drugs and behaviour: a review

(1) Bilateral olfactory bulbectomy (OB) produces a series of behavioural changes in the rat, characterised by hyperactivity and hyper-reactivity. It also produces an elevation of plasma 11-hydroxycorticosterone (11-OHCS). (2) Chronic treatment (10–14 days) of OB rats with anti-depressant drugs (amitriptyline, mianserin, viloxazine, nomifensine and iprindole) normalises the behavioural change and the 11-OHCS elevation. The mono-amine oxidase inhibitor, tranylcypromine, does not normalise these parameters. (3) Using two behavioural parameters (step-down avoidance testing and irritability), plus 11-OHCS measurements, it has proved possible to differentiate between anti-depressants, anti-anxiety agents, tranquilisers and central stimulants. OB therefore has potential as a screening method for differentiating between various classes of psychotropic drugs. (4) The quadracyclic anti-depressant, mianserin, proved negative in standard anti-depressant screening and a new derivative, GB-6582 proved positive in the OB model. GB-6582 is an efficient inhibitor of 5-hydroxytryptamine (5-HT) uptake. (5) The neurotoxin, 5–6 DHT, will mimic the behavioural and physiological effects of bulbectomy as will 5–7 DHT with prior treatment of the rat with desmethyl-imipramine, when these neurotoxins are injected directly into the olfactory bulb. The neurotoxin, 6-OHDA, injected into the bulb does not mimic the effects of OB. (6) GB-6582 when injected into the bulb prior to intra-bulbar 5–6 DHT, prevents the appearance of the behavioural and physiological effects of bulbectomy. (7) All the anti-depressants which normalise surgical bulbectomy, show the same effect with chemical bulbectomy induced by 5–6 DHT. (8) Following bulbectomy, neuroanatomical studies demonstrated degenerating fibres in: (a) the anterior hippocampus; (b) the corticomedial nucleii of the amygdala; (c) the bed nucleus of the stria terminalis and (d) the pre-optic area of the hypothalamus. (9) These brain areas are concerned with behavioural arousal, hypothalamic-adrenohypophyseal modulation and sexual behaviour. All these are adversely affected by bulbectomy. (10) The significance of these observations is discussed in terms of 5-HT-catecholamine interaction in the development of diseases of affect.     

Contextual learning increases dendrite complexity and EphrinB2 levels in hippocampal mouse neurons

Although the role of hippocampus in memory processing is well assessed, an association of experience-dependent behavioural modifications with hippocampal neuron morphological and biochemical changes deserves further characterisation. Here, we present evidence of dendritic alterations together with rapid accumulation of EphrinB2, a factor known to influence cell plasticity, in pyramidal neurons of the CA1 area of mouse hippocampus, during the formation of recent contextual fear memory. Male C57BL/6N mice exhibited a robust fear response 24 h after contextual and cued fear conditioning. At this time and in the absence of the memory test, conditioned mice showed morphological alterations in hippocampal and lateral amygdala neurons. Western blot analysis of extracts from conditioned but not pseudoconditioned or naive mice showed a specific increase in the amount of EphrinB2 in the hippocampus but not the cortex. However, levels of EphA4 receptor, known to interact trans-synaptically with EphrinB2, did not change upon conditioning in extracts from the same structures. Finally, immunohistochemical analysis of the hippocampus and amygdala of conditioned mice showed increased levels of EphrinB2 in pyramidal neurons of the CA1 area, when compared to pseudoconditioned and control mice. Such increase was not observed in other hippocampal areas or the amygdala. These results suggest that rapid accumulation of EphrinB2 in hippocampal CA1 neurons is involved in the behavioural and cellular modifications induced by contextual fear conditioning. A similar mechanism does not appear to occur in lateral amygdala neurons, in spite of the robust behavioural and cellular modifications induced in such structure by cued fear conditioning.     

Semaphorin 3A-mediated axon guidance regulates convergence and targeting of P2 odorant receptor axons

Semaphorins are known to play an important role in axon guidance of vertebrate olfactory sensory neurons to their targets in specific glomeruli of the olfactory bulb (OB). However, it is not clear how semaphorin-mediated guidance contributes to a systematic hierarchy of cues that govern the organization of this system. Because of the putative role that odorant receptor molecules such as P2 could play in establishing appropriate glomerular destinations for growing olfactory axons, we have also determined the spatial organization of P2 glomeruli in semaphorin 3A (Sema3A) mutant mice. First, in the postnatal OB of control and Sema3A(-/-) mice, we analysed the trajectories of olfactory axons that express the Sema3A receptor, neuropilin-1 (npn-1) and the positions of npn-1(+) glomeruli. Sema3A at the ventral OB midline guides npn-1(+) axons to targets in the lateral and medial OB. Absence of Sema3A permits many npn-1 axons to terminate aberrantly in the rostral and ventral OB. Second, in Sema3A(-/-) mice, many P2 axons are abnormally distributed throughout the ventral OB nerve layer and converge in atypical locations compared with littermate controls where P2 axons converge on stereotypically located lateral and medial glomeruli. In addition to their radically altered spatial distribution, P2 glomeruli in Sema3A(-/-) mice are significantly smaller and more numerous than in heterozygote littermates. These data show that Sema3A is an important repulsive olfactory guidance cue that establishes restricted npn-1(+) subcompartments in the olfactory bulb. Furthermore, Sema3A plays a key role in the convergence of axons expressing the odorant receptor P2 onto their appropriate targets.     

Neonatal lipopolysaccharide treatment has long‐term effects on monoaminergic and cannabinoid receptors in the rat

Brain inflammation in early life has been proposed to play important roles in the development of anxiety and psychosis‐related behaviors in adulthood, behaviors that rely on the integrity of dopamine and/or serotonin systems. Moreover recent behavioral and anatomical evidence suggests involvement of CB1 receptors in the control of emotion and mood. In this study, we determined the effects of neonatal LPS treatment on dopamine, serotonin, and cannabinoid receptor binding in adulthood. Rats were treated with the bacterial endotoxin lipopolysaccharide (LPS) on postnatal day (PND) 3 and 5. Dopamine D1, D2, serotonin 5HT1A, 5HT2A, and serotonin transporter and cannabinoid CB1 receptor binding across several brain regions were measured autoradiographically in adulthood (PND 85). Neonatal LPS treatment caused a significant increase in dopamine D2 in the nucleus accumbens and olfactory tubercle, a decrease in 5HT1A receptor binding in the hippocampus CA1 and ventromedial hypothalamus. A decrease in CB1 receptor binding after neonatal LPS was observed in the amygdala. Neonatal LPS had no significant impact on dopamine D1, serotonin 5HT2A or serotonin transporter binding in any of the brain regions examined. Our results suggest long lasting, region specific effects and differential impact on dopamine, serotonin and cannabinoid receptor systems following neonatal inflammation, that may form the basis for compromised anxiety and psychosis related behaviors. Synapse, 2013. © 2013 Wiley Periodicals, Inc.