These studies in fetal monkeys and ferrets show that the two fundamental types of thalamic GABA neuron populate the thalamus during widely separated developmental epochs. Those of the ventral thalamus (VT) and epithalamus (ET) appear very early in conjunction with the GABA cells of the substantia nigra, globus pallidus, and pretectum (PT). GABA neurons intrinsic to the dorsal thalamus (DT) appear later, long after proliferative activity has ceased in the wall of the third ventricle, after dorsal thalamic nuclei have differentiated and at the same time as principal neurons are acquiring a glutamatergic phenotype. The exact origins of the two waves of GABA cells are uncertain but some appear to arrive from extrinsic sources that include the ganglionic eminence (GE) of the basal forebrain.

Neuroanatomical tracers were injected into two functionally distinct areas in the lateral sulcus of macaque monkeys, the parietal ventral area (PV) and the second somatosensory area (S2). Three of the four injection sites were electrophysiologically determined by defining the receptive fields of neurons at the injection site prior to the placement of the anatomical tracers. Additionally, all locations were confirmed myeloarchitectonically. Labeled cell bodies and axon terminals were identified in the ipsilateral dorsal thalamus and related to nuclear boundaries in tissue stained for cytochrome oxidase (CO) and Nissl substance. Our results indicate that PV receives substantial input from the inferior division of the ventral posterior nucleus (VPi), the anterior pulvinar (Pla), and from the ventral portion of the magnocellular division of the mediodorsal nucleus (MDm), which also is interconnected with prefrontal cortex, the entorhinal cortex and the amygdala. S2 receives input predominantly from VPi, the ventral posterior superior nucleus (VPs), and Pla. These results indicate that PV and S2 are involved in processing inputs from deep receptors in the muscles and joints. Because PV and S2 receive little if any cutaneous input from the thalamus, cutaneous input to these fields must arise mainly through cortical connections. Connectional data supports the proposition that PV and S2 integrate motor and somatic information necessary for proprioception, goal directed reaching and grasping and tactile object identification. Further, PV may play a role in tactile learning and memory.

Thalamic afferents and efferents primarily use the neurotransmitter glutamate, which acts through a variety of ionotropic (NMDA, AMPA, kainate) and metabotropic receptors. The NMDAR is composed of multiple subunits, NR1 and NR2A-D. The obligatory NRl subunit is expressed as one of eight isoforms, due to the alternative splicing of exons 5, 21, and 22. Each NRl splice variant is functionally distinct. For instance, alternative splicing of exons 21 and 22 renders two C-terminal variants, which differentially associate with NR2 subunits and intracellular molecules such the PSD-95 family of proteins. These PSD proteins play a pivotal role in NMDAR function by linking NMDARs to the cytoskeleton and downstream signal-transducing enzymes that can directly modulate NMDAR function and/or promote NMDAR-associated intracellular events.

Previous work reported that NRl is by far the most abundant NMDAR subunit expressed in the primate thalamus. In the current study, we extend these findings first by determining which NRl isoforms are predominantly expressed in the thalamus. Secondly, we characterize the expression of the NMDAR-associated PSD molecules, such as PSD-95, in the thalamus. Using in situ hybridization, we examined expression of the transcripts encoding NRl isoforms containing exons 5, 21, or 22, and transcripts encoding a set of the most well-characterized NMDAR-associated PSD proteins (NF-L, PSD93, PSD95, SAP102, and Yotiao). NRl exon 22-containing isoforms are the most abundant subunit transcripts, accounting for 40–50% of the NRl isoforms expressed in most thalamic nuclei. We also found that NF-L is by far the most abundant PSD protein expressed in the thalamus, followed by PSD-95, which is moderately and heterogeneously expressed. SAP102 and PSD-93 were expressed at moderate to low levels, with negligible amounts of Yotiao transcript expression. The PSD-95 family of molecules are critical for NMDAR function in the cell, and this study is the first to provide a detailed description of the expression of these molecules in primate thalamus. Our results demonstrate that NRl splice variants and associated PSD proteins are heterogeneously expressed across the thalamus, which is likely related to the intracellular events that occur in different thalamic nuclei.

We examined the relationship between calbindin-D28k-defined subdivisions in the macaque inferior pulvinar and the patterns of afferent connections to cortical visual areas MT, V4 and V2. The subdivisions identified included the posterior (PIp), medial (PIm), central (PIc) and lateral (PIl) subdivisions. Projections to MT and V4 were largely segregated in the inferior pulvinar: projections to MT originated mainly from PIm, while projections to V4 originated mainly from PIl. In addition, weaker projections to MT were observed from PIp and PIc, and some projections from PIp to V4 were observed in one of two cases. Projections to V2 originated preferentially from PIl, with a lesser projection from PIc. No labeled cells were observed in PIm in five monkeys injected with various tracers into different regions of V2. Since most V2 injections were large enough to involve several neighboring stripe-like compartments, these findings suggest that PIm does not project to V2 compartments associated with neither dorsal nor ventral cortical processing streams. Cells projecting to V4 were not strictly segregated from those projecting to V2 in neither PIl nor PIc, suggesting that inferior pulvinar projections do not map the position of visual areas in the cortical mantle.

Intracellular recordings from thalamocortical (TC) neurons in the ventrolateral (VL) nucleus as well as paired intracellular recordings from TC-VL neurons and area 4 cortical neurons under ketamine-xylazine anesthesia were performed to study changes in hyperpolarization-rebound sequences evoked by successive stimuli to the dorsal thalamus at different frequencies and the impact of these changes at the cortical level. The cellular mechanisms of such changes in synaptic networks connecting TC with cortical neurons are relevant for short-term plasticity during low-frequency oscillatory activities. The progressive decrease in hyperpolarization of TC cells in response to single thalamic stimulus above a certain frequency (generally >1 Hz) and to pulse-trains at 10 Hz was mainly due to synaptic factors and not to mechanisms intrinsic to TC cells, as revealed by comparing responses evoked by synaptic volleys to those elicited by hyperpolarizing current pulses mimicking the synaptically evoked hyperpolarization-rebound sequence. The decreased hyperpolarization to repetitive synaptic volleys, leading to a decreased number of action potentials in the post-inhibitory spike-burst, had an impact on cortical activities, being matched by a decreased rebound depolarization of cortical cell during repetitive augmenting responses. The alterations in hyperpolarization-rebound sequences upon repetitive stimulation, probably resulting from the decreased efficacy of connections between thalamic reticular (RE) neurons to TC connections, results in the dampening of activities sustaining normal, and possibly paroxysmal, oscillations in the TC network. Our results suggest that this phenomenon should be taken into account when analyzing complex activities, such as physiological and pathological oscillations.

This work is focused on the study of neuronal circuits arising from the rodent caudal intralaminar nuclei and their presumed role on basal ganglia function. Emphasis was placed on the analysis of the architecture of thalamostriatal and thalamo-subthalamic projections in albino rats. Our major interest was to elucidate whether thalamic inputs were related to projection neurons or local circuit neurons within targeted structures (striatum and subthalamic nucleus). Projections coming from the parafascicular nucleus (PF) to the striatum displayed a patchy organization throughout the matrix compartment. These patches are composed by dense terminal axonal arborizations, often containing striatal neurons projecting to the entopeduncular nucleus (ENT) (medial globus pallidus in primates) and neurons projecting to the substantia nigra reticulata (SNR). The thalamostriatal projections under scrutiny were also seen to be in register with all the major classes of striatal interneurons (nitrergic neurons, neurons containing the calcium binding protein parvalbumin (PV) and cholinergic interneurons). Subthalamic neurons projecting to the ENT are the presumed postsynaptic target for fibers coming from the sensorimotor part (dorsolateral) of the PF. In summary, glutamatergic axons arising from the PF might exert a dual control of the striatal output, either by directly exciting striatal projection neurons or indirectly by means of a previous synaptic contact onto an striatal interneuron which in turn modulates the activity of projection neurons. Furthermore, thalamic inputs can also gain access to basal ganglia output nuclei via subthalamo-pallidal projecting neurons, neurons receiving glutamatergic thalamo-subthalamic projections. Thus, activation of either circuit has an opposite physiological effect on the basal ganglia output nucleus. Taken together, these data suggest that the PF may influence neuronal activity in the direct and indirect circuits and could be considered as an additional component of the basal ganglia motor loops.

Nucleus-specific expression of five gene transcripts related to the inhibitory, gamma-aminobutyric acid (GABA), neurotransmitter system (GABAA receptor subunits αl, α5, β2, γ2, and 67kDa glutamic acid decarboxylase (GAD67)), and of seven transcripts related to the excitatory, glutamatergic, system (GluR2,4–6, NR1 and NR2A, and α-type II calcium/calmodulin-dependent protein kinase (CAMKII-α)), were examined by quantitative in situ hybridization histochemistry in the thalami of brains from normal controls and from patients suffering from schizophrenia. Although there is evidence for cell loss and functional hypoactivity in the thalamus in schizophrenia, it was striking that quantitative levels and expression patterns of the transcripts studied showed only minor differences between schizophrenics and matched controls. Expression patterns of the transcripts had many similarities to the patterns seen in the thalamus of non-human primates. Abundant GABAA-αl, GABAA-(β2, and GABAA-γ2 subunit mRNAs levels were found in most nuclei. Expression levels of the NMDA receptor subunit, NR1, were higher than those seen for NR2A, AMPA (GluR2 and 4) or kainate (GluR5 and 6) receptor subunit mRNAs. Expression of NR2A mRNA was extremely low. CAMKII-α expression was restricted to glutamatergic neurons. Unlike in monkeys, GluR2 subunit mRNA expression was higher than GluR4 expression. These expression patterns form the beginning of a comprehensive database of patterns of gene expression at high resolution in the human forebrain in health and disease.

Voltage-sensitive dye imaging (VDI) of cortical activation patterns generated by electrical stimulation of thalamocortical afferents axons at different frequencies was studied, in vitro, using mouse brain slices. The study demonstrated that thalamocortical afferent axons stimulation could follow frequencies as high as 120 Hz without marked reduction. By contrast the power spectral density amplitude ratio in cortical layer 4 demonstrated a rapidly sigmoidal reduction at frequencies above 60 Hz. Similar findings were obtained with direct cortical afferent axons stimulation that obviated possible interactions at thalamic level. As pre-synaptic afferent field potentials, simultaneously recorded with the VDI at cortical level, followed higher stimulation frequency, it is concluded that cortical activity reduction is secondary to synaptic transmission failure. This interpretation agrees with the result from deep-brain stimulation (DBS) in humans in which high-frequency stimulation produces comparable therapeutic results, as does stereotaxic brain lesioning.

Disruptions in the thalamocortical circuit have been related to several psychiatric disorders, such as schizophrenia and obsessive-compulsive disorders. The dopaminergic/GABAergic afferents to the limbic thalamocortical circuit originate in the ventral tegmental area (VTA) and play a crucial role in the regulation of the normal cognitive functions mediated by this circuit. Moreover, it has been shown that the dopaminergic modulatory system is altered in schizophrenics. Despite the strong clinical and behavioral evidence of the importance of the thalamocortical circuit and the mesocortical dopamine (DA) system for normal cognitive function, little is known about the basic synaptic interactions between the thalamus and VTA. This research hypothesized that VTA stimulation would evoke DAergic and/or GABAergic-mediated responses in the MD thalamic neurons. Using intracellular recordings in vivo, it was found that VTA stimulation evoked short latency EPSPs in 73% of the recorded MD neurons and IPSPs-like responses in 16% of the MD cells. The nature of the VTA-MD projection was explored using DAergic and GABAergic drugs. It was found that the indirect DAergic agonist amphetamine affects the spontaneous and VTA-mediated responses recorded in the MD thalamus. These results indicate that the VTA projection contributes to the modulation of MD activity and that the disruption of such modulation may be relevant in neuropsychiatry disorders.

A series of 49 cases with difficult to control seizures and non-candidates for ablation of the epileptic focus has been treated with electrical stimulation of the centromedian thalamic nuclei (ESCM).

Selected cases were: (1) epilepsia partialis continua (EPC) (n = 5); (2) partial complex seizures (n = 16); (3) bilateral frontal parasagittal seizures (n = 6); (4) Lennox-Gastaut syndrome (n = 22). All patients had four contact electrodes placed bilaterally through frontal parasagittal burr holes and guided by ventriculograms. Plotting of electrodes on sagittal and frontal sections of the Schaltenbrand and Bailey’s atlas permitted to determine their location. Electrodes were left externalized for periods of weeks to months to carry out the following tests. (1) Recordings of spontaneous seizures occurring during wakefulness and sleep. (2) Electrophysiological confirmation of their position by means of recruiting responses and desynchronization induced by low and high frequency stimulation. (3) Effects of high frequency stimulation on interictal and ictal activities. Electrodes were internalized and connected to a subcutaneous pulse generator programmed for alternating right and left ESCM 1 min ON and 4 min OFF at 60–130 Hz, 0.21–0.45 ms, 3–5 V forward and backward for 24 h per day. Repeated EEG recordings and a calendar of seizures were used for follow-up from 1 to 9 years.

CM paroxysmal discharges followed the initiation of seizures in cortical areas, occurred simultaneously with spike wave (SKW) complexes in cortical areas in Lennox-Gastaut syndrome and preceded the initiation of cortical SKW and clinical seizures in typical absences. Low frequency stimulation (6–8 cps) induced recruiting responses that were associated with those electrodes that produced best seizure control. Good to excellent results were obtained in cases of EPC and Lennox-Gastaut syndrome and on generalized tonic clonic convulsions (GTCs) and atypical absences (AA) with tonic or clonic components.

Consequently, we came to the conclusions that the CM participates in the propagation of most seizure types and also in the genesis of some of them and that ESCM is a safe and useful alternative for the treatment of some of the most difficult cases of uncontrollable seizures.