Regulation of learned vocal behavior by an auditory motor cortical nucleus in juvenile zebra finches.

In the process of song learning, songbirds such as the zebra finch shape their initial soft and poorly formed vocalizations (subsong) first into variable plastic songs with a discernable recurring motif and then into highly stereotyped adult songs. A premotor brain area critically involved in plastic and adult song production is the cortical nucleus HVC. One of HVC's primary afferents, the nucleus interface of the nidopallium (NIf), provides a significant source of auditory input to HVC. However, the premotor involvement of NIf has not been extensively studied yet. Here we report that brief and reversible pharmacological inactivation of NIf in juvenile birds leads to transient degradation of plastic song toward subsong, as revealed by spectral and temporal song features. No such song degradation is seen following NIf inactivation in adults. However, in both juveniles and adults NIf inactivation leads to a transient decrease in song stereotypy. Our findings reveal a contribution of NIf to song production in juveniles that agrees with its known role in adults in mediating thalamic drive to downstream vocal motor areas during sleep.

Spikes and bursts in two types of thalamic projection neurons differentially shape sleep patterns and auditory responses in a songbird.

In mammals, the thalamus plays important roles for cortical processing, such as relay of sensory information and induction of rhythmical firing during sleep. In neurons of the avian cerebrum, in analogy with cortical up and down states, complex patterns of regular-spiking and dense-bursting modes are frequently observed during sleep. However, the roles of thalamic inputs for shaping these firing modes are largely unknown. A suspected key player is the avian thalamic nucleus uvaeformis (Uva). Uva is innervated by polysensory input, receives indirect cerebral feedback via the midbrain, and projects to the cerebrum via two distinct pathways. Using pharmacological manipulation, electrical stimulation, and extracellular recordings of Uva projection neurons, we study the involvement of Uva in zebra finches for the generation of spontaneous activity and auditory responses in premotor area HVC (used as a proper name) and the downstream robust nucleus of the arcopallium (RA). In awake and sleeping birds, we find that single Uva spikes suppress and spike bursts enhance spontaneous and auditory-evoked bursts in HVC and RA neurons. Strong burst suppression is mediated mainly via tonically firing HVC-projecting Uva neurons, whereas a fast burst drive is mediated indirectly via Uva neurons projecting to the nucleus interface of the nidopallium. Our results reveal that cerebral sleep-burst epochs and arousal-related burst suppression are both shaped by sophisticated polysynaptic thalamic mechanisms.

Group I metabotropic glutamate receptors enable two distinct forms of long-term depression in the rat dentate gyrus in vivo.

The existence of long-term depression (LTD) in the dentate gyrus of freely moving rats, as well as the contribution of different types of metabotropic glutamate receptors (mGluRs) to this form of plasticity, has been the subject of much debate. Here, we describe two distinct forms of mGluR-dependent hippocampal LTD in the dentate gyrus of freely moving adult rats. LTD, induced by low-frequency stimulation (LFS) of the medial perforant path (LFS-LTD), was prevented by antagonism of the phospholipase C-coupled receptors, mGluR1 but not mGluR5. Chemical LTD, induced by intracerebral application of the group I mGluR agonist (R,S)-3,5-dihydroxyphenylglycine, was blocked by antagonism of both mGluR5 and mGluR1. Selective activation of mGluR5, using (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG), also led to chemical LTD. To test whether LFS-LTD and chemical LTD share common induction mechanisms, we applied LFS following the induction of chemical LTD by CHPG (CHPG-LTD). Surprisingly, LFS impaired CHPG-LTD. Further analysis revealed that induction of CHPG-LTD led to altered calcium dynamics sufficient for its reversal by LFS. We found that LTD induced by (R,S)-3,5-dihydroxyphenylglycine, but not by CHPG, is impaired by N-methyl-d-aspartate receptor antagonism. Both forms of chemical LTD strongly require calcium influx through L-type voltage-gated calcium channels. This contrasts with previous findings that LFS-LTD in the dentate gyrus is both N-methyl-d-aspartate receptor and voltage-gated calcium channel independent. LFS-LTD and LTD induced by group I mGluR agonists thus appear to comprise distinct forms of LTD that require the activation of specific group I mGluRs and recruit calcium from different sources.

Group III metabotropic glutamate receptor-mediated, chemically induced long-term depression differentially affects cell viability in the hippocampus.

In vivo, activation of group III metabotropic glutamate (mGlu) receptors leads to a reduction of basal synaptic transmission in the hippocampus, and depending on the experimental conditions in vitro, leads to neuroprotection or neurotoxicity. Here, the cellular response to cerebral application of L(+)-2-amino-4-phosphonobutanoic acid (AP4) was investigated in the CA1 region and dentate gyrus of freely moving rats. Drugs were applied via the lateral ventricle, and electrophysiological measurements were obtained via chronically implanted electrodes. AP4 produced a slowly developing depression of evoked responses in both hippocampal regions which lasted for over 4 h. Effects could be reversed by application of high frequency tetanus. Histological evaluation, 4 h or 7 d, following a single, acute AP4 injection into the lateral cerebral ventricle showed that AP4-mediated synaptic depression either amplified (CA1) or attenuated (dentate gyrus) excitotoxic neuronal death, strongly depending on the sub-region investigated. Effects were long-lasting, being still evident 7 days after AP4 application. In both hippocampal areas, the effects obtained were subtle, however, with the CA1 region being more potently affected. Interestingly, effects in the dentate gyrus comprised a slight enhancement of live cell number coupled with deterioration in cell area, suggesting that cell proliferation triggered by group III mGlu receptor activation may have masked neurotoxic effects mediated by activation of this receptor. These results show that although AP4 induces a slow-onset synaptic depression in both sub-regions, cell viability is differentially influenced by activation of group III mGlu receptors in the CA1 region and dentate gyrus.

Investigations of the protein synthesis dependency of mGluR-induced long-term depression in the dentate gyrus of freely moving rats.

Hippocampal long-term depression (LTD) comprises an activity-dependent weakening of synaptic strength. In this study we compared persistent LTD induced by the group I mGluR agonist, DHPG, or the group III mGluR agonist, AP4, in the dentate gyrus of freely moving rats. The role of protein translation, using the translation inhibitors, anisomycin and emetine, was also investigated. Potentials were evoked from medial perforant path-dentate gyrus granule cell synapses of male Wistar rats by means of chronically implanted electrodes. Immediately after intracerebral (ventricular) application of DHPG or AP4 robust LTD (>24 h) occurred. Paired-pulse analysis during LTD, and application of mGluR antagonists after stabilisation of depression, supported that LTD genuinely occurred and that the depression was not a consequence of persistence of the agonists at the synapse. Application of a protein synthesis inhibitor 2 h prior to DHPG injection inhibited the expression of LTD (from ca. 6 h post-injection) but did not affect LTD induced by AP4. These data highlight differences in chemical LTD elicited by group I and group III mGluRs. Whereas AP4-induced LTD may arise as a result of modulation of presynaptic glutamate release mechanisms, the protein synthesis dependency of DHPG-induced LTD suggests an additional postsynaptic expression mechanism for this phenomenon.

Pharmacological antagonism of metabotropic glutamate receptor 1 regulates long-term potentiation and spatial reference memory in the dentate gyrus of freely moving rats via N-methyl-D-aspartate and metabotropic glutamate receptor-dependent mechanisms.

Group I metabotropic glutamate receptors (mGluRs) are critically required for multiple forms of hippocampal synaptic plasticity in vivo. The role of the receptor subtype mGluR1 in long-term potentiation (LTP) and learning is unclear. We examined the contribution of mGluR1 to hippocampal LTP and spatial learning using the selective antagonist (S)-(+)-alpha-amino-4carboxy-2-methylbenzene-acetic acid (LY367385). Male Wistar rats were chronically implanted with recording and stimulating electrodes to enable measurement of evoked potentials from medial perforant path-dentate gyrus granule cell synapses. An injection cannula was inserted into the ipsilateral cerebral ventricle to enable drug application. Experiments were begun 10 days after the implantation procedure. We induced a robust LTP which lasted over 25 h with a 200-Hz tetanization. Injections of LY367385 at all concentrations under investigation (4-32 nmol in a 5-microL injection volume) did not affect basal synaptic transmission. In contrast, we observed a dose-dependent impairment of LTP expression: LY367385 (4 nmol) had no effect on LTP induction, whereas 8 and 16 nmol LY367385 reduced both LTP induction and expression, suggestive of an interaction with N-methyl-d-aspartate receptors. We assessed the effects of daily LY367385 application (8 nmol) on performance in an eight-arm radial maze. LY367385-treated rats showed deficits in reference but not working memory performance compared with vehicle-treated controls. Rearing, grooming and locomotor activity were unaffected by LY367385. These data suggest an important role for mGluR1 in LTP and learning and highlight the specific significance of this mGluR subtype for reference memory.

Regulation by metabotropic glutamate receptor 5 of LTP in the dentate gyrus of freely moving rats: relevance for learning and memory formation.

Group I metabotropic glutamate (mGlu) receptors play a critical role in the regulation of hippocampal long-term potentiation (LTP) in vivo. Little is known, however, about the contribution of the individual subtypes mGlu1 and mGlu5 to learning processes and LTP. We investigated the involvement of mGlu5 in hippocampal LTP and spatial learning using the selective antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). Rats were chronically implanted with recording and stimulating electrodes to enable measurement of evoked potentials from the medial perforant path - dentate gyrus granule cell synapses. An injection cannula was inserted into the ipsilateral cerebral ventricle to enable drug application. Experiments were begun 10 days subsequent to the implantation procedure. Robust LTP which lasted for over 25 h was generated using 200 Hz tetanization. MPEP, applied in concentrations which did not affect basal synaptic transmission, dose-dependently impaired the induction and expression of LTP. Application of MPEP 5 min after tetanization inhibited late LTP (>24 h). The effects of daily MPEP application on performance in an eight-arm radial maze were evaluated. MPEP-treated rats showed deficits in reference and working memory performance compared to vehicle-treated controls. Rearing, grooming and locomotor activity were unaffected in MPEP-treated animals. These data highlight the importance of mGlu5 for both LTP and spatial learning and emphasize the significance of these receptors for information storage on both synaptic and behavioural levels.