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To explore the mechanism underlying the imitation of finger gestures, we devised a simple imitation task in which the patients were instructed to replicate finger configurations in two conditions: one in which they could see their hand (visual feedback: VF) and one in which they could not see their hand (non-visual feedback: NVF). Patients with left brain damage (LBD) or right brain damage (RBD), respectively, were categorized into two groups based on their scores on the imitation task in the NVF condition: the impaired imitation groups (I-LBD and I-RBD) who failed two or more of the five patterns and the control groups (C-LBD and C-RBD) who made one or no errors. We also measured the movement-production times for imitation. The I-RBD group performed significantly worse than the C-RBD group even in the VF condition. In contrast, the I-LBD group was selectively impaired in the NVF condition. The I-LBD group performed the imitations at a significantly slower rate than the C-LBD group in both the VF and NVF conditions. These results suggest that impaired imitation in patients with LBD is partly due to an abnormal integration of visual and somatosensory information based on the task specificity of the NVF condition.

Olfaction plays an important role in social recognition in most mammals. Central arginine vasopressin (AVP) plays a role in this olfaction-based recognition. The high level of expression of AVP receptors in the accessory olfactory bulb (AOB) at the first relay of the vomeronasal system highlights the importance of AVP signaling at this stage. We therefore analyzed the effects of AVP on the synaptic plasticity of glutamatergic transmission from mitral cells to granule cells in AOB slices from male mice. To monitor the strength of the glutamatergic transmission, we measured the maximal initial slope of the lateral olfactory tract-evoked field potential, which represents the granule cell response to mitral cell activation. AVP paired with 100-Hz stimulation that only produced short-term potentiation enhanced the induction of long-term potentiation (LTP) in a dose-dependent manner. AVP-paired LTP was blocked by the selective AVP receptor 1a (AVPR1a) antagonist, d(CH2)5[Tyr(Me)2]AVP (Manning compound), but not by the AVPR1b antagonist SSR149415, and it was mimicked by the selective AVPR1a agonist [Phe2, Ile3, Orn8]-vasopressin. We further examined the effect of AVP on the reciprocal transmission between mitral and granule cells by stimulating a mitral cell and recording the evoked inhibitory postsynaptic currents (IPSCs) from the same cell using conventional whole-cell patch-clamp techniques. AVP reduced the reciprocal IPSCs triggered by endogenous glutamate release from the excited mitral cell. These results suggest that AVP promotes the induction of LTP at the mitral-to-granule cell synapse via the activation of AVPR1a through an as-yet-to-be-determined mechanism in the AOB of male mice.

Epigenetic mechanisms play an important role in memory formation and synaptic plasticity. Specifically, histone-associated heterochromatin undergoes changes in structure during the early stages of long-term memory formation. In keeping with the classical conditioning paradigm, young rats have been shown to exhibit aversion to an odor stimulus initially presented during foot shock. We previously showed that synaptic plasticity at the dendrodendritic synapses between mitral and granule cells in the olfactory bulb (OB) underlies this aversive olfactory learning. However, the epigenetic mechanisms involved are not well characterized. Therefore, we examined whether intrabulbar infusion of trichostatin A (TSA), a histone deacetylase inhibitor, facilitates olfactory learning in young rats. TSA infusion during odor-shock training enhanced a conditioned odor aversion in a dose-dependent manner and prolonged the learned aversion. Western blot and immunohistochemical analyses showed that the level of histone H4 acetylation significantly increased until 4 h after odor-shock training in both mitral and granule cells in the OB, whereas histone H3 acetylation returned to the control level at 2 h after the training. We also obtained evidence that TSA infusion elevated acetylation of histone H4 or H3. Furthermore, in vitro electrophysiological analysis using slices of the OB revealed that application of TSA significantly enhanced the long-term potentiation induced in synaptic transmission from mitral to granule cells at dendrodendritic synapses. Taken together, these results provide evidence that histone H4 and H3 acetylation in the OB is an epigenetic mechanism associated with aversive olfactory learning in young rats.

Cholinergic modulation of spontaneous GABAergic currents (mIPSC) was studied using whole-cell patch methods in mouse accessory olfactory bulb slices. Carbachol (above 100 microM) administration produced an increase in the mIPSC frequency in mitral cells, but did not affect the responses of mitral cells to GABA. The carbachol effect persisted in the presence of combined ionotropic and metabotropic glutamatergic receptor antagonists. The carbachol effect was reduced by the muscarinic receptor type-1 and -4 (M1 and M4) antagonist pirenzepine (10 microM), but not by the M2 and M4 antagonist himbacine (10 microM). The KCNQ/Kv7 potassium channel openers retigabine (80 microM) and diclofenac (300 microM) blocked the carbachol action, while the KCNQ potassium channel blocker XE-911 (20 microM) increased the mIPSC frequency. XE-911's action persisted in the presence of glutamate receptor blockers. In the presence of carbachol, mIPSCs were abolished by Ni (200 microM), while being insensitive to the calcium channel blocker nimodipine (30 microM), suggesting a role for R-type calcium channels in the GABA release. These results suggest that carbachol closed KCNQ channels by stimulating M1 receptors on granule cell dendrites, and the resulting depolarized and unstable membrane promoted calcium influx, thus increasing the GABA release. The possible role of acetylcholine in facilitating formation of a pheromone memory in mice is also discussed.

The mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) cascade is an important contributor to synaptic plasticity that underlies learning and memory. ERK activation by the MAPK/ERK kinase (MEK) leading to cyclic-AMP response element binding protein (CREB) phosphorylation is implicated in the formation of long-term memory. We have demonstrated that CREB phosphorylation in the olfactory bulb (OB) is important for aversive olfactory learning in young rats, yet whether MAPK/ERK functions as an upstream regulator are necessary for this olfactory learning remains to be determined. Therefore, we addressed this issue using behavioral and Western blot analyses. The MEK inhibitor PD98059 was continuously infused into the OB of postnatal day 11 rat pups during a 30-min training session regarding the pairing of citral odor and foot shock. On the following day, the time spent in the part of the apparatus where the odor was present was measured as an index of odor aversion. PD98059 impaired olfactory learning in a dose-dependent manner without affecting memory retention 1 h after training. We further tested whether odor-shock training leads to MAPK/ERK activation in the OB and defines the time course of the activation. Phosphorylated ERKs (P-ERKs) 1 and 2 were significantly increased for 60 min after the training without changes in total ERKs 1 and 2. By contrast, intrabulbar infusion of PD98059 during the training significantly reduced P-ERKs 1 and 2 as well as phosphorylated CREB without any effects on the total ERKs or CREB. Taken together with the previous findings, these results indicate that the MAPK/ERK–CREB pathway is required for the long-term, but not the short-term, facilitation process of aversive olfactory learning in young rats.

Reciprocal dendrodendritic synapses between mitral and granule cells in the accessory olfactory bulb have been implicated in a specialized form of olfactory learning in mice, in which a female forms a memory to the pheromonal signal of the male that mates with her. Relatively little is known, however, about the mechanism of synaptic transmission at the reciprocal synapses. We analyzed synaptic currents generated in accessory olfactory bulb mitral cells in slice preparations with the patch-clamp technique in nystatin-perforated whole-cell configuration. A brief (5–20-ms) depolarizing voltage step from −70 to 0 mV applied to a single mitral cell evoked GABA A receptor-mediated inhibitory postsynaptic currents. The inhibitory postsynaptic currents persisted in the presence of tetrodotoxin, indicating that the inhibitory postsynaptic current in mitral cells can be elicited through purely dendritic interactions. The inhibitory postsynaptic currents were greatly enhanced by washout of extracellular Mg 2+ . In Mg 2+ -free solution, the N -methyl- D -aspartate (NMDA) receptor antagonist D , L -2-amino-5-phosphonovaleric acid greatly reduced the inhibitory postsynaptic currents, whereas the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-(1 H ,4 H )-dione (CNQX) slightly reduced them. These data demonstrate that NMDA receptors play an important role in the generation of dendrodendritic inhibition in mitral cells of the mouse accessory olfactory bulb.

In this study, we examined the effect of acute capsaicin injection on nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d, a histochemical index of nitric oxide, NO, synthase) and Fos expression in the rat pituitary gland. Compared with vehicle, capsaicin significantly activated Fos expression in the anterior and intermediate lobes. In addition, capsaicin-treated rats showed a significant upregulation of NADPH-d in the anterior and neural lobes. Pretreatment of the animals with a specific NO synthase inhibitor, N ω -nitro- l -arginine methyl ester ( l -NAME), significantly attenuated the capsaicin-induced Fos expression in the anterior and intermediate lobes. These observations suggest that NO is a key regulator of the acute effect of capsaicin on the pituitary gland.

Glial cells regulate some neural functions which depend on the homeostatic maintenance of extracellular calcium within narrow physiological ranges. In this study, the presence of microglia-specific ionized calcium binding adaptor molecule 1 (Iba1) was examined in the mouse olfactory bulb. A heterogenous pattern of Iba1-positive cells expression was observed between the main and accessory olfactory bulbs (MOB and AOB, respectively). While Iba1 was almost uniformly expressed among the laminae of the MOB, its expression showed spatial variations from the anterior to the posterior regions of the AOB. Double immunofluorescence was used to confirm that Iba1 is not expressed in astrocytes which stained for glial fibrillary acidic protein. Since Iba1 may mediate calcium signals in microglia, the observations suggest a potential involvement of Iba1 and hence microglia in olfactory bulb function and/or homeostasis. Together with our previous observation, this provides further support of a bulbar neuron–glia system of potential physiological significance.

An electrophysiological study was performed with mice lacking complexin II, a presynaptic protein. The long-term potentiation (LTP) by high-frequency stimulation, recorded in the hippocampal CA1 area, was decreased in complexin II-lacking mice (CPXII KO mice). The overall postsynaptic currents elicited by low frequency stimulation on the Schaffer collateral/commissural fibers in the hippocampal CA1 pyramidal cells were not different between wild-type and mutant mice. Excitatory postsynaptic currents (EPSCs) recorded in the presence of 50 microM bicuculline and inhibitory postsynaptic currents (IPSCs) recorded in the presence of 50 microM AP-5 (DL-2-amino-5-phosphonopentanoic acid) + 30 microM CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) were also identical between wild-types and mutants. Furthermore, the EPSCs following repetitive stimulation (10 Hz) in CPXII KO mice did not show any difference with wild-types. These findings suggest that complexin II does not play a crucial role in ordinary neural transmission, short-term synaptic plasticity or synaptic transmission during high-frequency repetitive stimulation. Therefore, the protein is thought to be involved in the LTP process following tetanic stimulation, including the induction and/or maintenance of the LTP.

The exact nature of how nitric oxide (NO) acts in the regulation of milk ejection during lactation is not clearly understood at the moment. In this study, we have examined the effect of drugs which spontaneously release NO (sodium nitroprusside, SNP) or inhibit the NO synthase (NOS) enzyme (Nω-nitro- l -arginine, l -NA) on the activity of some hypothalamic and functionally associated nuclei using Fos expression as an index of neuronal activation. Lactating rats received intracerebroventricular injection of SNP, l -NA or vehicle (saline) just before they were reunited with their pups after a 12-h period of separation and allowed to suckle for 2 h. The difference in the total pup body weight before and after the period of suckling was used as a functional end-point of milk transfer. Central injection of SNP in conscious rats significantly inhibited Fos expression in the paraventricular nucleus (PVN), supraoptic nucleus (SON), periventricular and preoptic nuclei and also decreased pup body weight compared with saline- or l -NA-injected rats. Urethane-anesthetized animals, compared with their conscious counterparts, showed increased Fos expression in the PVN and SON. However, Fos expression in the PVN of the anesthetized animals was attenuated by l -NA injection compared with SNP and saline injection. Taken together with an earlier finding that SNP disrupts the milk ejection burst of oxytocinergic neurons, these observations suggest that NO may act within the neuron(s) possibly to alter the mechanism(s) regulating the periodic neuronal burst activity during lactation.

The present report describes neurosteroid modulation of olfactory bulb function by examining the effects of intrabulbar infusion of dehydroepiandrosterone sulfate (DHEAS), a neurohormone discovered in rat brain, on field potentials in the granule cell layer evoked by paired-pulse stimulation of the mouse lateral olfactory tract. Infusion of DHEAS (5 nmol) significantly decreased the test response without affecting the conditioning response. As a consequence, DHEAS selectively potentiated paired-pulse depression, which is believed to be due to granule cell-mediated inhibition of the mitral/tufted cells. The granule-to-mitral/tufted dendrodendritic synapse is GABAergic. Taken together, these results suggest that DHEAS potentiates the GABAergic dendrodendritic inhibition exerted by the granule cells on the mitral/tufted cells.

The effects of electrical stimulation of the hypothalamus paraventricular nucleus on the spontaneous firing of mitral and granule cells in the main olfactory bulb were examined in ovariectomized female rats under urethane anaesthesia. High-frequency stimulation (0.5-1.0 mA, 10-20 pulses at 100 Hz) of the paraventricular nucleus produced inhibitory responses in 80% of mitral cells tested and excitatory responses in 74% of granule cells tested, with latencies ranging from 2 to 150 s. Both responses were blocked by infusions into the olfactory bulb of [d(CH2)5, Tyr(Me)2]ornithine-vasotocin (10 pmol), an oxytocin antagonist, and mimicked by intracerebroventricular infusions (0.2 or 0.4 nmol) or microiontophoretic applications of oxytocin but not by intracerebroventricular infusions of vasopressin (1 or 2 nmol). Infusions of 0.5% lignocaine, a local anaesthetic, into either the medial olfactory tract or the medial forebrain bundle failed to block the responses of mitral and granule cells to the stimulation. Unilateral transections at various levels between the bulb and the paraventricular nucleus also failed to block the responses. There were cases in which significant responses of mitral and granule cells to the stimulation required 60 or more pulses after the lignocaine infusions or transections, however. These results suggest that oxytocin originating in the hypothalamic paraventricular nucleus reaches the olfactory bulb following its release partly into the cerebrospinal fluid and acts to decrease olfactory processing.

The plexiform and granule cell layers of the female mouse accessory olfactory bulb, whose synaptic activities are modified by pheromonal inputs after mating, contain one of the highest densities of nitric oxide synthase in the brain. We tested the hypothesis that exogenous nitric oxide administration can, in principle, permit the formation of a specific pheromonal memory without mating by acting in synergy with bulbar neurotransmitter(s) to enhance long-lasting increase in gain of the mitral-granule cell dendrodendritic synapse. Two infusions of sodium nitroprusside (5 nmol; 0.5 microliters) into the accessory olfactory bulb activated recognition without mating. A single infusion produced no recognition. This memory is specific to the pheromones to which the females were exposed during sodium nitroprusside infusions because strange male pheromones evoked a significant pregnancy failure rate. Furthermore, the memory formation is dependent on coincident activation by pheromonal inputs and sodium nitroprusside infusions, since drug infusions in the absence of male pheromones permitted a significant pregnancy block on test exposure. The alpha-adrenergic antagonist phentolamine prevented a sodium nitroprusside-mediated memory formation. In females with depleted bulbar noradrenergic innervation by specific neurotoxin (6-hydroxydopamine) injection into the medial olfactory striae or the accessory olfactory bulb, sodium nitroprusside infusions failed to induce memory formation. The procedure itself apparently did not interfere with the occurrence of pregnancy. These results demonstrate that exogenous administration of nitric oxide can induce a pheromone-specific olfactory memory without mating, and that this memory is mediated, at least in part, by noradrenaline.

The gaseous neurotransmitter molecule nitric oxide (NO) has recently generated a lot of interest on account of its possible physiological role in several models of learning and memory, both in vitro and in vivo. The presence of its synthesizing enzyme has been reported in the granule cell and external plexiform layers of the accessory olfactory bulb (AOB) in mice and rats. We have tested the effect of different doses of the nitric oxide synthase inhibitor, N ω -nitro- l -arginine applied locally and peripherally, on the formation of olfactory recognition memory in the context of pregnancy block in mice. Local infusions of 5, 10, and 40 nmol of the NOS inhibitor into the AOB failed to prevent memory formation of the stud male without affecting the effectiveness of the strange male to induce pregnancy block. Peripheral administration of the NOS inhibitor produced a pregnancy block rate that was linearly related to the dose regardless of whether or not exposure to the familiar or no male subsequently followed. This suggests that the effect of peripheral administration of the NOS inhibitor on memory formation could not be assessed using this experimental paradigm. The observations made in this study do not enable us to envisage any critical or primary physiological role for NO in this memory model. Its role, at best, may be modulatory and not obligatory.

In virgin rats, odour cues from pups are aversive and maternal behaviour is not elicited until this aversion is overcome. Oxytecin as a neurohypophyseai peptide has long been recognized for its effects on labour and milk ejection. This traditional view of oxytocin has been extended to include a network of nonpituitary projections. Oxytocin fibres, arising principally from parvocellular neurons in the hypothalamic paraventricular nucleus (PVN), have been found in limbic and autonomic centres. The close proximity of many oxytocin fibres to the cerebroventricular system has also been found. Vaginocervical stimulation releases oxytocin, which further promotes uterine contraction, an event which is associated with a dramatic increase in maternal responsiveness. Intracerebroventricular (ICV) infusions of oxytocin induce the rapid activation of maternal behaviour in non-parturient rats; oxytocin is increased in the olfactory bulb of sheep during parturition. These findings raise the possibility that oxytocin decreases olfactory processing in the olfactory bulb, thereby permitting parturient rats to approach their pups. We examined the effects of electrical stimulation of the PVN (0.5-1.0 mA, 100 Hz, 10-20 pulses) on the spontaneous firing of mitral and granule cells in the main olfactory bulb in urethane-anaesthetized female rats. Of mitrai cells tested, 80% showed inhibitory responses to PVN stimulation, with latencies ranging from 2 to 150 s. In contrast, 74% of granule cells tested showed excitatory responses to PVN stimulation, with latencies ranging from 2 to 145 s. Both the inhibitory and excitatory responses were blocked by local infusions of [d(CHs)s,Tyr(Me)2]-ornitine-vasotocin (10 pmol), an oxytocin antagonist, into the olfactory bulb. Mitral and

On mating with a stud male, virgin female mice from an olfactory memory to this male which is essential to their reproductive success. Failure to form this memory results in the stud male being treated as strange, and hence, his pheromones block pregnancy. This study investigates the duration of the olfactory memory, and the factors which determine this. The results show that a single prolonged exposure to the male during mating forms a life-long olfactory memory trace unless pregnancy ensues. In the event of pregnancy the olfactory memory fades significantly faster, an effect which can be replicated by implants of oestradiol in non-pregnant females. Anatomical studies indicate that neurogenesis of the vomeronasal receptors is enhanced during pregnancy, an event which we interpret as being important for the duration of this olfactory memory.

Electrical stimulation of the rat A1 noradrenergic region produced orthodromic inhibition (34%), excitation (23%) or excitation-inhibition sequence (25%) of the spontaneous activity of phasically firing units in the paraventricular nucleus of the hypothalamus (PVH). Excitatory responses could be distinguised into two types on the basis of their latency and duration. Both the primary and post-excitatory inhibitory responses were significantly attenuated by intravenous injection of propranolol, a β-adrenoceptor antagonist, whereas neither type of excitatory response was affected.

Seventy neurons in the ventrolateral medulla oblongata were antidromically activated by electrical stimulation of the preoptic and anterior hypothalamic area (POA/AHA) in female rats under urethane anesthesia. These identified cells were located within and adjacent to the nucleus reticularis lateralis and could be readily distinguished into at least two types of neurons, designated as ‘fast’ and ‘slow’ cells, on the basis of their waveform and conduction velocity.

Fifteen neurons in the region of the subfornical organ (SFO) were antidromically activated by electrical stimulation of the paraventricular nucleus (PVN) in the rat. Electrical stimulation of the lateral hypothalamic area (LHA) excited the activity of 9 of the identified units, but did not affect the remaining units. The excitatory response of the identified units was blocked by microiontophoretically (MIPh) applied saralasin (Sar), an angiotensin II (ANGII) antagonist, but not by atropine (Atr), a muscarinic antagonist. These results suggest that the LHA has an excitatory influence on the activity of neurons in the region of the SFO with efferent projections to the PVN and that the influence may be mediated by ANGII receptors.

Estradiol benzoate administered to ovariectomized female rats significantly elevated the mean spontaneous firing rate and frequency of successful antidromic propagation into the somatodendritic spike and significantly reduced the strength of post-stimulus inhibition in presumed A1 noradrenergic neurons projecting directly to the preoptic and anterior hypothalamic area. The occurrence of both antidromic spikes and post-stimulus inhibition of the majority of these neurons was completely abolished by the injection of 6-hydroxydopamine but not by 5, 7-dihydroxytryptamine directly into the medial forebrain bundle.

Electrical stimulation of the rat A1 noradrenergic region produced excitation (77%) of the activity of putative vasopressin (VP)-secreting neurons in the paraventricular nucleus (PVN) and produced excitation (4%), inhibition (26%) and excitation-inhibition (11%) of the activity of PVN neurons that were not antidromically identified by neurohypophysial stimulation. The excitatory response of putative VP-secreting neurons was blocked by microiontophoretically applied phentolamine, an α-adrenoceptor antagonist, but not by timolol, a β-adrenoceptor antagonist. The inhibitory response of unidentified PVN neurons, on the other hand, was blocked by timolol, but not by phentolamine.

Female mice which have mated and are subsequently exposed to the odour (pheromones) of a strange male undergo hormonal changes resulting in a block to their pregnancy. The fact that the stud male's odours can also block pregnancies, that is other than his own, implies the formation of a memory or some form of recognition process by the female for this male's pheromones at the time of mating. The purpose of this study was to evaluate the effect of microinfusions of drugs which interfere with neural transmission, into the accessory olfactory bulbs. This was carried out immediately after mating over a 4-h period during which the "memory" to the stud male's pheromones is formed. Infusions of the alpha-blocker, phentolamine, blocked the formation of the olfactory memory, while the GABA receptor blocker, bicuculline, itself blocked pregnancy, but was without effect on memory formation. Protein synthesis inhibition or calpain inactivation in the accessory bulb was without effect on memory formation at any of the doses used. These studies demonstrate that GABAergic transmitter blockade in the accessory olfactory bulb at the time of mating can prevent subsequent blastocyst implantation some 3 days later, while alpha-noradrenergic blockade can prevent the formation of an olfactory memory to the stud male.