Nucleus reticularis neurons mediate diverse inhibitory effects in thalamus

Detailed information regarding the contribution of individual γ-aminobutyric acid (GABA)-containing inhibitory neurons to the overall synaptic activity of single postsynaptic cells is essential to our understanding of fundamental elements of synaptic integration and operation of neuronal circuits. For example, GABA-containing cells in the thalamic reticular nucleus (nRt) provide major inhibitory innervation of thalamic relay nuclei that is critical to thalamocortical rhythm generation. To investigate the contribution of individual nRt neurons to the strength of this internuclear inhibition, we obtained whole-cell recordings of unitary inhibitory postsynaptic currents (IPSCs) evoked in ventrobasal thalamocortical (VB) neurons by stimulation of single nRt cells in rat thalamic slices, in conjunction with intracellular biocytin labeling. Two types of monosynaptic IPSCs could be distinguished. “Weak” inhibitory connections were characterized by a significant number of postsynaptic failures in response to presynaptic nRt action potentials and relatively small IPSCs. In contrast, “strong” inhibition was characterized by the absence of postsynaptic failures and significantly larger unitary IPSCs. By using miniature IPSC amplitudes to infer quantal size, we estimated that unitary IPSCs associated with weak inhibition resulted from activation of 1–3 release sites, whereas stronger inhibition would require simultaneous activation of 5–70 release sites. The inhibitory strengths were positively correlated with the density of axonal swellings of the presynaptic nRt neurons, an indicator that characterizes different nRt axonal arborization patterns. These results demonstrate that there is a heterogeneity of inhibitory interactions between nRt and VB neurons, and that variations in gross morphological features of axonal arbors in the central nervous system can be associated with significant differences in postsynaptic response characteristics.

Representation of sound localization cues in the auditory thalamus of the barn owl

Barn owls can localize a sound source using either the map of auditory space contained in the optic tectum or the auditory forebrain. The auditory thalamus, nucleus ovoidalis (N.Ov), is situated between these two auditory areas, and its inactivation precludes the use of the auditory forebrain for sound localization. We examined the sources of inputs to the N.Ov as well as their patterns of termination within the nucleus. We also examined the response of single neurons within the N.Ov to tonal stimuli and sound localization cues. Afferents to the N.Ov originated with a diffuse population of neurons located bilaterally within the lateral shell, core, and medial shell subdivisions of the central nucleus of the inferior colliculus. Additional afferent input originated from the ipsilateral ventral nucleus of the lateral lemniscus. No afferent input was provided to the N.Ov from the external nucleus of the inferior colliculus or the optic tectum. The N.Ov was tonotopically organized with high frequencies represented dorsally and low frequencies ventrally. Although neurons in the N.Ov responded to localization cues, there was no apparent topographic mapping of these cues within the nucleus, in contrast to the tectal pathway. However, nearly all possible types of binaural response to sound localization cues were represented. These findings suggest that in the thalamo-telencephalic auditory pathway, sound localization is subserved by a nontopographic representation of auditory space.

Cooperative functions of the reaper and head involution defective genes in the programmed cell death of Drosophila central nervous system midline cells

In Drosophila, the chromosomal region 75C1–2 contains at least three genes, reaper (rpr), head involution defective (hid), and grim, that have important functions in the activation of programmed cell death. To better understand how cells are killed by these genes, we have utilized a well defined set of embryonic central nervous system midline cells that normally exhibit a specific pattern of glial cell death. In this study we show that both rpr and hid are expressed in dying midline cells and that the normal pattern of midline cell death requires the function of multiple genes in the 75C1–2 interval. We also utilized the P[UAS]/P[Gal4] system to target expression of rpr and hid to midline cells. Targeted expression of rpr or hid alone was not sufficient to induce ectopic midline cell death. However, expression of both rpr and hid together rapidly induced ectopic midline cell death that resulted in axon scaffold defects characteristic of mutants with abnormal midline cell development. Midline-targeted expression of the baculovirus p35 protein, a caspase inhibitor, blocked both normal and ectopic rpr- and hid-induced cell death. Taken together, our results suggest that rpr and hid are expressed together and cooperate to induce programmed cell death during development of the central nervous system midline.

Xenopus Kielin: A dorsalizing factor containing multiple chordin-type repeats secreted from the embryonic midline

The midline tissues are important inductive centers of early vertebrate embryos. By signal peptide selection screening, we isolated a secreted factor, Kielin, which contains multiple cys-rich repeats similar to those in chordin (Chd). Expression of Kielin starts at midgastrula stages in the notochord and is detected in the floor plate of neurula embryos. Kielin is induced in mesoderm and in ectoderm by nodal-related genes. Chd is sufficient to activate Kielin expression in mesoderm whereas Shh or HNF-3β in addition to Chd is required for induction in ectoderm. Kielin has a distinct biological activity from that of Chd. Injection of Kielin mRNA causes dorsalization of ventral marginal zone explants and expansion of MyoD expression in neurula embryos. Unlike Chd, Kielin does not efficiently induce neural differentiation of animal cap ectoderm, suggesting that the activity of Kielin is not simply caused by BMP4 blockade. Kielin is a signaling molecule that mediates inductive activities of the embryonic midline.

Neuroimaging evidence implicating cerebellum in the experience of hypercapnia and hunger for air

Recent neuroimaging and neurological data implicate cerebellum in nonmotor sensory, cognitive, vegetative, and affective functions. The present study assessed cerebellar responses when the urge to breathe is stimulated by inhaled CO2. Ventilation changes follow arterial blood partial pressure CO2 changes sensed by the medullary ventral respiratory group (VRG) and hypothalamus, entraining changes in midbrain, pons, thalamus, limbic, paralimbic, and insular regions. Nearly all these areas are known to connect anatomically with the cerebellum. Using positron emission tomography, we measured regional brain blood flow during acute CO2-induced breathlessness in humans. Separable physiological and subjective effects (air hunger) were assessed by comparisons with various respiratory control conditions. The conjoint physiological effects of hypercapnia and the consequent air hunger produced strong bilateral, near-midline activations of the cerebellum in anterior quadrangular, central, and lingula lobules, and in many areas of posterior quadrangular, tonsil, biventer, declive, and inferior semilunar lobules. The primal emotion of air hunger, dissociated from hypercapnia, activated midline regions of the central lobule. The distributed activity across the cerebellum is similar to that for thirst, hunger, and their satiation. Four possible interpretations of cerebellar function(s) here are that: it subserves implicit intentions to access air; it provides predictive internal models about the consequences of CO2 inhalation; it modulates emotional responses; and that while some cerebellar regions monitor sensory acquisition in the VRG (CO2 concentration), others influence VRG to adjust respiratory rate to optimize partial pressure CO2, and others still monitor and optimize the acquisition of other sensory data in service of air hunger aroused vigilance.

A visceral pain pathway in the dorsal column of the spinal cord

A limited midline myelotomy at T10 can relieve pelvic cancer pain in patients. This observation is explainable in light of strong evidence in support of the existence of a visceral pain pathway that ascends in the dorsal column (DC) of the spinal cord. In rats and monkeys, responses of neurons in the ventral posterolateral thalamic nucleus to noxious colorectal distention are dramatically reduced after a lesion of the DC at T10, but not by interruption of the spinothalamic tract. Blockade of transmission of visceral nociceptive signals through the rat sacral cord by microdialysis administration of morphine or 6-cyano-7-nitroquinoxaline-2,3-dione shows that postsynaptic DC neurons in the sacral cord transmit visceral nociceptive signals to the gracile nucleus. Retrograde tracing studies in rats demonstrate a concentration of postsynaptic DC neurons in the central gray matter of the L6-S1 spinal segments, and anterograde tracing studies show that labeled axons ascend from this region to the gracile nucleus. A similar projection from the midthoracic spinal cord ends in the gracile and cuneate nuclei. Behavioral experiments demonstrate that DC lesions reduce the nocifensive responses produced by noxious stimulation of the pancreas and duodenum, as well as the electrophysiological responses of ventral posterolateral neurons to these stimuli. Repeated regional blood volume measurements were made in the thalamus and other brain structures in anesthetized monkeys in response to colorectal distention by functional MRI. Sham surgery did not reduce the regional blood volume changes, whereas the changes were eliminated by a DC lesion at T10.

Localization of alpha type II calcium calmodulin-dependent protein kinase at glutamatergic but not gamma-aminobutyric acid (GABAergic) synapses in thalamus and cerebral cortex.

The alpha subunit of type II calcium/calmodulin-dependent protein kinase (CAM II kinase-alpha) plays an important role in longterm synaptic plasticity. We applied preembedding immunocytochemistry (for CAM II kinase-alpha) and postembedding immunogold labeling [for glutamate or gamma-aminobutyric acid (GABA)] to explore the subcellular relationships between transmitter-defined axon terminals and the kinase at excitatory and inhibitory synapses in thalamus and cerebral cortex. Many (but not all) axon terminals ending in asymmetric synapses contained presynaptic CAM II kinase-alpha immunoreactivity; GABAergic terminals ending in symmetric synapses did not. Postsynaptically, CAM II kinase-alpha immunoreactivity was associated with postsynaptic densities of many (but not all) glutamatergic axon terminals ending on excitatory neurons. CAM II kinase-alpha immunoreactivity was absent at postsynaptic densities of all GABAergic synapses. The findings show that CAM II kinase-alpha is selectively expressed in subpopulations of excitatory neurons and, to our knowledge, demonstrate for the first time that it is only associated with glutamatergic terminals pre- and postsynaptically. CAM II kinase-alpha is unlikely to play a role in plasticity at GABAergic synapses.

G protein activation kinetics and spillover of gamma-aminobutyric acid may account for differences between inhibitory responses in the hippocampus and thalamus.

We have developed a model of gamma-aminobutyric acid (GABA)ergic synaptic transmission mediated by GABAA and GABAB receptors, including cooperativity in the guanine nucleotide binding protein (G protein) cascade mediating the activation of K+ channels by GABAB receptors. If the binding of several G proteins is needed to activate the K+ channels, then only a prolonged activation of GABAB receptors evoked detectable currents. This could occur if strong stimuli evoked release in adjacent terminals and the spillover resulted in prolonged activation of the receptors, leading to inhibitory responses similar to those observed in hippocampal slices. The same model also reproduced thalamic GABAB responses to high-frequency bursts of stimuli. In this case, prolonged activation of the receptors was due to high-frequency release conditions. This model provides insights into the function of GABAB receptors in normal and epileptic discharges.

On the actions that one nerve cell can have on another: Distinguishing “drivers” from “modulators”

When one nerve cell acts on another, its postsynaptic effect can vary greatly. In sensory systems, inputs from “drivers” can be differentiated from those of “modulators.” The driver can be identified as the transmitter of receptive field properties; the modulator can be identified as altering the probability of certain aspects of that transmission. Where receptive fields are not available, the distinction is more difficult and currently is undefined. We use the visual pathways, particularly the thalamic geniculate relay for which much relevant evidence is available, to explore ways in which drivers can be distinguished from modulators. The extent to which the distinction may apply first to other parts of the thalamus and then, possibly, to other parts of the brain is considered. We suggest the following distinctions: Cross-correlograms from driver inputs have sharper peaks than those from modulators; there are likely to be few drivers but many modulators for any one cell; and drivers are likely to act only through ionotropic receptors having a fast postsynaptic effect whereas modulators also are likely to activate metabotropic receptors having a slow and prolonged postsynaptic effect.

Immediate and simultaneous sensory reorganization at cortical and subcortical levels of the somatosensory system

The occurrence of cortical plasticity during adulthood has been demonstrated using many experimental paradigms. Whether this phenomenon is generated exclusively by changes in intrinsic cortical circuitry, or whether it involves concomitant cortical and subcortical reorganization, remains controversial. Here, we addressed this issue by simultaneously recording the extracellular activity of up to 135 neurons in the primary somatosensory cortex, ventral posterior medial nucleus of the thalamus, and trigeminal brainstem complex of adult rats, before and after a reversible sensory deactivation was produced by subcutaneous injections of lidocaine. Following the onset of the deactivation, immediate and simultaneous sensory reorganization was observed at all levels of the somatosensory system. No statistical difference was observed when the overall spatial extent of the cortical (9.1 ± 1.2 whiskers, mean ± SE) and the thalamic (6.1 ± 1.6 whiskers) reorganization was compared. Likewise, no significant difference was found in the percentage of cortical (71.1 ± 5.2%) and thalamic (66.4 ± 10.7%) neurons exhibiting unmasked sensory responses. Although unmasked cortical responses occurred at significantly higher latencies (19.6 ± 0.3 ms, mean ± SE) than thalamic responses (13.1 ± 0.6 ms), variations in neuronal latency induced by the sensory deafferentation occurred as often in the thalamus as in the cortex. These data clearly demonstrate that peripheral sensory deafferentation triggers a system-wide reorganization, and strongly suggest that the spatiotemporal attributes of cortical plasticity are paralleled by subcortical reorganization.

The type 2 iodothyronine deiodinase is expressed primarily in glial cells in the neonatal rat brain

Thyroid hormone plays an essential role in mammalian brain maturation and function, in large part by regulating the expression of specific neuronal genes. In this tissue, the type 2 deiodinase (D2) appears to be essential for providing adequate levels of the active thyroid hormone 3,5,3′-triiodothyronine (T3) during the developmental period. We have studied the regional and cellular localization of D2 mRNA in the brain of 15-day-old neonatal rats. D2 is expressed in the cerebral cortex, olfactory bulb, hippocampus, caudate, thalamus, hypothalamus, and cerebellum and was absent from the white matter. At the cellular level, D2 is expressed predominantly, if not exclusively, in astrocytes and in the tanycytes lining the third ventricle and present in the median eminence. These results suggest a close metabolic coupling between subsets of glial cells and neurons, whereby thyroxine is taken up from the blood and/or cerebrospinal fluid by astrocytes and tanycytes, is deiodinated to T3, and then is released for utilization by neurons.

Head direction cells and episodic spatial information in rats without a hippocampus

To successfully navigate through the environment animals rely on information concerning their directional heading and location. Many cells within the postsubiculum and anterior thalamus discharge as a function of the animal’s head direction (HD), while many cells in the hippocampus discharge in relation to the animal’s location. We placed lesions in the hippocampus and recorded from HD cells in the postsubiculum and anterior thalamus. Lesions of the hippocampus did not disrupt the HD cell signal in either brain area, indicating that the HD cell signal must be generated by structures external to the hippocampus. In addition, each cell’s preferred firing direction remained stable across days when the lesioned animal was placed into a novel environment. This stability appeared to weaken after several weeks of nonexposure to the new enclosure for two out of five animals, and subsequently recorded cells from these two animals established a new angular relationship between the familiar and novel environments. Our results suggest that extra-hippocampal structures are capable of creating and maintaining a novel representation of the animal’s environmental context. This representation shares features in common with mnemonic processes involving episodic memory that until now were assumed to require an intact hippocampus.

γ-Aminobutyric acid type B receptor-dependent burst-firing in thalamic neurons: A dynamic clamp study

Synchronized network responses in thalamus depend on phasic inhibition originating in the thalamic reticular nucleus (nRt) and are mediated by the neurotransmitter γ-aminobutyric acid (GABA). A suggested role for intra-nRt connectivity in inhibitory phasing remains controversial. Recently, functional GABA type B (GABAB) receptors were demonstrated on nRt cells, and the slow time course of the GABAB synaptic response seems ideally suited to deinactivate low-threshold calcium channels. This promotes burst firing, a characteristic feature of synchronized responses. Here we investigate GABAB-mediated rebound burst firing in thalamic cells. Whole-cell current-clamp recordings were obtained from nRt cells and somatosensory thalamocortical relay cells in rat brain slices. Synthetic GABAB inhibitory postsynaptic potentials, generated by a hybrid computer–neuron synapse (dynamic clamp), triggered rebound low-threshold calcium spikes in both cell types when peak inhibitory postsynaptic potential hyperpolarization was greater than −92 mV. The threshold inhibitory postsynaptic potential conductance for rebound burst generation was comparable in nRt (7 nS) and thalamocortical (5 nS) cells. However, burst onset in nRt (1 s) was considerably delayed compared with thalamocortical (0.6 s) cells. Thus, GABAB inhibitory postsynaptic potentials can elicit low-threshold calcium spikes in both relay and nRt neurons, but the resultant oscillation frequency would be faster for thalamocortical–nRt networks (3 Hz) than for nRt–nRt networks (1–2 Hz). We conclude, therefore, that fast (>2 Hz) GABAB-dependent thalamic oscillations are maintained primarily by reciprocal connections between excitatory and inhibitory cells. These findings further indicate that when oscillatory neural networks contain both recurrent and reciprocal inhibition, then distinct population frequencies may result when one or the other type of inhibition is favored.