Mediodorsal thalamic function in scene memory in rhesus monkeys.
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Three monkeys were trained preoperatively in a scene memory task which is analogous, in some ways, to human episodic memory. The same animals were also trained in object-reward association memory. Following bilateral ablations of almost the entire magnocellular division of the mediodorsal thalamic nucleus, the animals were impaired both in scene memory and in object-reward association memory. These results, combined with recent results in object recognition memory from monkeys with mediodorsal thalamic lesions, show that the impairment produced by this lesion is more general, affecting a broader range of memory tasks, than the impairment which is produced in monkeys by lesions restricted to the hippocampus-fornix-mamillary system. It is also more severe than the effect of lesions limited to the medial part of the magnocellular division of the mediodorsal thalamic nucleus. These findings extend the evidence that the magnocellular division of the mediodorsal thalamic nucleus has an important and general role in memory, and they are consistent with the proposal that lesions of the magnocellular division of that nucleus have their effect by disrupting the function of prefrontal cortex. (+info)
Netrin-1 promotes thalamic axon growth and is required for proper development of the thalamocortical projection.
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The thalamocortical axon (TCA) projection originates in dorsal thalamus, conveys sensory input to the neocortex, and has a critical role in cortical development. We show that the secreted axon guidance molecule netrin-1 acts in vitro as an attractant and growth promoter for dorsal thalamic axons and is required for the proper development of the TCA projection in vivo. As TCAs approach the hypothalamus, they turn laterally into the ventral telencephalon and extend toward the cortex through a population of netrin-1-expressing cells. DCC and neogenin, receptors implicated in mediating the attractant effects of netrin-1, are expressed in dorsal thalamus, whereas unc5h2 and unc5h3, netrin-1 receptors implicated in repulsion, are not. In vitro, dorsal thalamic axons show biased growth toward a source of netrin-1, which can be abolished by netrin-1-blocking antibodies. Netrin-1 also enhances overall axon outgrowth from explants of dorsal thalamus. The biased growth of dorsal thalamic axons toward the internal capsule zone of ventral telencephalic explants is attenuated, but not significantly, by netrin-1-blocking antibodies, suggesting that it releases another attractant activity for TCAs in addition to netrin-1. Analyses of netrin-1 -/- mice reveal that the TCA projection through the ventral telencephalon is disorganized, their pathway is abnormally restricted, and fewer dorsal thalamic axons reach cortex. These findings demonstrate that netrin-1 promotes the growth of TCAs through the ventral telencephalon and cooperates with other guidance cues to control their pathfinding from dorsal thalamus to cortex. (+info)
Dorsal rhizotomy changes the spontaneous neuronal activity of nuclei in the medial thalamus.
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The aim of this study was to examine the influence of unilateral dorsal root section at the cervicothoracic level of the spinal cord on the spontaneous neuronal activity of medial thalamic nuclei in the rat. Single unit extracellular recordings from thalamic nuclei, nc. parafascicularis and nc. centralis lateralis, were obtained with glass micropipettes. The abnormal bursting activity of these nuclei following deafferentation was registered, although a correlation between the occurrence of this activity and the degree of autotomy behavior was not found. Such bursts were never observed in the studied thalamic nuclei of control rats. (+info)
The effect of SB-269970, a 5-HT(7) receptor antagonist, on 5-HT release from serotonergic terminals and cell bodies.
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1. The presence of 5-HT(7) receptor mRNA and protein in 5-HT neurons suggests that this receptor may act as a 5-HT autoreceptor. In this study, the effect of the 5-HT(7) receptor antagonist, SB-269970 ((R)-1-[3-hydroxy phenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine), was investigated on 5-HT release in the guinea-pig and rat cortex and the rat dorsal raphe nucleus (DRN), using the techniques of in vitro [(3)H]-5-HT release or fast cyclic voltammetry, respectively. 2. Cortical slices were loaded with [(3)H]-5-HT and release was evoked by electrical stimulation. 5-CT inhibited the evoked release of [(3)H]-5-HT in a concentration-dependent manner. SB-269970 had no significant effect on [(3)H]-5-HT release while the 5-HT(1B) receptor antagonist, SB-224289 significantly potentiated [(3)H]-5-HT release. In addition, SB-269970 was unable to attenuate the 5-CT-induced inhibition of release while SB-224289 produced a rightward shift of the 5-CT response, generating estimated pK(B) values of 7.8 and 7.6 at the guinea-pig and rat terminal 5-HT autoreceptors respectively. 3. Rat DRN slices were electrically stimulated and the evoked 5-HT efflux detected by voltammetric analysis. 8-OH-DPAT inhibited evoked 5-HT efflux and was fully reversed by WAY 100635. SB-269970 had no effect on either 5-HT efflux per se or 8-OH-DPAT-induced inhibition of 5-HT efflux. In addition, 5-CT inhibited 5-HT efflux in a concentration-dependent manner. SB-269970 was unable to attenuate the 5-CT-induced inhibition of 5-HT efflux. 4. In conclusion, we were unable to provide evidence to suggest a 5-HT autoreceptor role for 5-HT(7) receptors. However, investigations with more selective 5-HT(7) receptor agonists are needed to confirm the data reported here. (+info)
Status epilepticus causes necrotic damage in the mediodorsal nucleus of the thalamus in immature rats.
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Status epilepticus (StE) in immature rats causes long-term functional impairment. Whether this is associated with structural alterations remains controversial. The present study was designed to test the hypothesis that StE at an early age results in neuronal loss. StE was induced with lithium-pilocarpine in 12-d-old rats, and the presence of neuronal damage was investigated in the brain from 12 hr up to 1 week later using silver and Fluoro-Jade B staining techniques. Analysis of the sections indicated consistent neuronal damage in the central and lateral segments of the mediodorsal nucleus of the thalamus, which was confirmed using adjacent cresyl violet-stained preparations. The mechanism of thalamic damage (necrosis vs apoptosis) was investigated further using TUNEL, immunohistochemistry for caspase-3 and cytochrome c, and electron microscopy. Activated microglia were detected using OX-42 immunohistochemistry. The presence of silver and Fluoro-Jade B-positive degenerating neurons in the mediodorsal thalamic nucleus was associated with the appearance of OX-42-immunopositive activated microglia but not with the expression of markers of programmed cell death, caspase-3, or cytochrome c. Electron microscopy revealed necrosis of the ultrastructure of damaged neurons, providing further evidence that the mechanism of StE-induced damage in the mediodorsal thalamic nucleus at postnatal day 12 is necrosis rather than apoptosis. Finally, these data together with previously described functions of the medial and lateral segments of the mediodorsal thalamic nucleus suggest that some functions, such as adaptation to novelty, might become compromised after StE early in development. (+info)
Prefrontal cortex long-term potentiation, but not long-term depression, is associated with the maintenance of extinction of learned fear in mice.
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Considerable efforts have been made to identify changes of brain synaptic plasticity associated with fear conditioning. However, for both clinical applications and our fundamental understanding of memory processes, it appears also necessary to investigate synaptic plasticity related to extinction. We previously showed that extinction of freezing to a tone conditioned stimulus (CS; previously paired with footshock) in mice results in a sequence of depression and potentiation of synaptic efficacy in the medial prefrontal cortex (mPFC). These data as well as those from lesion studies suggest that the direction of changes in prefrontal synaptic plasticity may modulate extinction of learned fear. To test this, we analyzed the effects of low-frequency stimulation (LFS) and high-frequency stimulation (HFS) of the mediodorsal thalamic nucleus, known to induce prefrontal long-term depression (LTD) and potentiation (LTP), respectively, on extinction. We found that maintenance of the depression phase, using thalamic LFS, was associated with resistance to extinction. Thalamic HFS applied before extinction testing had no effect on the rate of extinction. However, 1 week follow-up tests revealed that the memory of extinction was intact in these mice (with prefrontal LTP) and in control mice displaying prefrontal LTP-like changes, whereas control mice that did not exhibit such changes displayed a return of freezing to the CS. The results suggest that after extinction the lack of depression-LTP-like conversion sequence in the mPFC synaptic efficacy may profoundly alter the process of consolidation. (+info)
Mediodorsal thalamic lesions impair trace eyeblink conditioning in the rabbit.
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Rabbits received lesions of the mediodorsal nucleus of the thalamus (MDN) or sham lesions and were subjected to classical eyeblink (EB) and heart rate (HR) conditioning. All animals received trace conditioning, with a.5-sec tone conditioned stimulus, a .5-sec trace period, and a 50-msec periorbital shock unconditioned stimulus. Animals with MDN lesions acquired the EB conditioned response (CR) more slowly than sham-lesioned animals. However, previous studies have shown that MDN damage does not affect delay conditioning using either .5-sec or 1-sec interstimulus intervals. The lesions had no significant effect on the HR CR. These results suggest that information processed by MDN and relayed to the prefrontal cortex is required for somatomotor response selection under nonoptimal learning conditions. (+info)
Up-regulation of glutamate receptors in nucleus tractus solitarii underlies potentiation of baroreceptor reflex by heat shock protein 70.
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Whereas induction of the 70-kDa heat shock protein (HSP70) in the nucleus tractus solitarii (NTS), the terminal site in the brain stem for primary baroreceptor afferents, augments baroreceptor reflex (BRR) response, the underlying cellular and molecular mechanism is essentially unexplored. In Sprague-Dawley rats, we evaluated the hypothesis that HSP70 may potentiate BRR response by up-regulating the molecular synthesis and functional expression of glutamate receptors in the NTS. Animals subjected to brief hyperthermic heat shock (HS; 42 degrees C for 15 min) exhibited augmented expression of NR1 or NR2A subunit of N-methyl-D-aspartate (NMDA) receptors, GluR1 or GluR4 subunits of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors and KA1 subunit of kainate receptors in the NTS. Intriguingly, this up-regulation of glutamate receptors was preceded by an increase in HSP70 expression at the NTS. The HS-induced augmentation in responsiveness of barosensitive NTS neurons to transient hypertension or potentiation of BRR response was discernibly blunted by MK-801 or 6-cyano-7-nitroquinoxaline-2,3-dione. Bilateral microinjection into the NTS of an antisense hsp70 oligonucleotide (50 pmol) before HS significantly suppressed the induced expression of HSP70 or the increase in glutamate receptor subunits in the dorsal medulla and discernibly attenuated the potentiation of BRR response. Control microinjection into the NTS of sense or scrambled hsp70 oligonucleotide (50 pmol) was ineffective. These findings suggest that HSP70 induced by HS may enhance BRR response by up-regulating the molecular synthesis and functional expression of NR1 or NR2A subunit of NMDA receptors and GluR1, GluR4, or KA1 subunit of non-NMDA receptors in the NTS. (+info)