Deep Cortical Laminae Research Articles

Lamina-specific cortical dynamics in human visual and sensorimotor cortices.

Distinct anatomical and spectral channels are thought to play specialized roles in the communication within cortical networks. While activity in the alpha and beta frequency range (7 - 40 Hz) is thought to predominantly originate from infragranular cortical layers conveying feedback-related information, activity in the gamma range (>40 Hz) dominates in supragranular layers communicating feedforward signals. We leveraged high precision MEG to test this proposal, directly and non-invasively, in human participants performing visually cued actions. We found that visual alpha mapped onto deep cortical laminae, whereas visual gamma predominantly occurred more superficially. This lamina-specificity was echoed in movement-related sensorimotor beta and gamma activity. These lamina-specific pre- and post- movement changes in sensorimotor beta and gamma activity suggest a more complex functional role than the proposed feedback and feedforward communication in sensory cortex. Distinct frequency channels thus operate in a lamina-specific manner across cortex, but may fulfill distinct functional roles in sensory and motor processes.

Non-invasive laminar inference with MEG: Comparison of methods and source inversion algorithms

Magnetoencephalography (MEG) is a direct measure of neuronal current flow; its anatomical resolution is therefore not constrained by physiology but rather by data quality and the models used to explain these data. Recent simulation work has shown that it is possible to distinguish between signals arising in the deep and superficial cortical laminae given accurate knowledge of these surfaces with respect to the MEG sensors. This previous work has focused around a single inversion scheme (multiple sparse priors) and a single global parametric fit metric (free energy). In this paper we use several different source inversion algorithms and both local and global, as well as parametric and non-parametric fit metrics in order to demonstrate the robustness of the discrimination between layers. We find that only algorithms with some sparsity constraint can successfully be used to make laminar discrimination. Importantly, local t-statistics, global cross-validation and free energy all provide robust and mutually corroborating metrics of fit. We show that discrimination accuracy is affected by patch size estimates, cortical surface features, and lead field strength, which suggests several possible future improvements to this technique. This study demonstrates the possibility of determining the laminar origin of MEG sensor activity, and thus directly testing theories of human cognition that involve laminar- and frequency-specific mechanisms. This possibility can now be achieved using recent developments in high precision MEG, most notably the use of subject-specific head-casts, which allow for significant increases in data quality and therefore anatomically precise MEG recordings. SectionAnalysis methods. ClassificationsSource localization: inverse problem; Source localization: other.

Quantitative relations between BOLD responses, cortical energetics, and impulse firing.

The blood oxygen level-dependent (BOLD) functional magnetic resonance imaging signal arises as a consequence of changes in blood flow and oxygen usage that in turn are modulated by changes in neural activity. Much attention has been given to both theoretical and experimental aspects of the energetics but not to the neural activity. Here we identify the best energetic theory for the steady-state BOLD signal on the basis of correct predictions of experimental observations. This theory is then used, together with the recently determined relationship between energetics and neural activity, to predict how the BOLD signal changes with activity. Unlike existing treatments, this new theory incorporates a nonzero baseline activity in a completely consistent way and is thus able to account for both sustained positive and negative BOLD signals. We also show that the increase in BOLD signal for a given increase in activity is significantly smaller the larger the baseline activity, as is experimentally observed. Furthermore, the decline of the positive BOLD signal arising from deeper cortical laminae in response to an increase in neural firing is shown to arise as a consequence of the larger baseline activity in deeper laminae. Finally, we provide quantitative relations integrating BOLD responses, energetics, and impulse firing, which among other predictions give the same results as existing theories when the baseline activity is zero. NEW & NOTEWORTHY We use a recently established relation between energetics and neural activity to give a quantitative account of BOLD dependence on neural activity. The incorporation of a nonzero baseline neural activity accounts for positive and negative BOLD signals, shows that changes in neural activity give BOLD changes that are smaller the larger the baseline, and provides a basis for the observed inverse relation between BOLD responses and the depth of cortical laminae giving rise to them.

Phase and amplitude correlations in resting-state activity in human stereotactical EEG recordings

Inter-areal interactions of neuronal oscillations may be a key mechanism in the coordination of anatomically distributed neuronal processing. In humans, invasive stereo-electroencephalography (SEEG) is emerging as a reference method for electrophysiological recordings because of its excellent spatial and temporal resolution. It could thus be also considered an optimal method for mapping neuronal inter-areal interactions. However, the common bipolar (BP) referencing of SEEG data may both confuse signals from distinct sources and suppress true neuronal interactions whereas the alternative monopolar (MP) reference yields data contaminated by volume conduction. We advance here a novel referencing scheme for SEEG data where electrodes in grey matter are referenced to closest white-matter (CW) electrodes. Using a 22 subject cohort and these three referencing schemes, we observed that both inter-areal phase and amplitude correlations decayed as function of distance and frequency but remained significant and stable across distances up to 10cm. Furthermore, we found that deep and superficial cortical laminae exhibit distinct spectral profiles of oscillation power as well as distinct patterns of inter-areal phase and amplitude interactions. These effects were qualitatively similar in MP and CW but distorted with BP referencing. Importantly CW was not influenced by the apparent large-scale volume conduction inherent to MP. We thus demonstrate here that with CW referencing, the superior anatomical accuracy of SEEG can be leveraged to yield accurate quantification and qualitatively novel insight into phase and amplitude interactions in human brain activity.

Phase-amplitude coupling and interlaminar synchrony are correlated in human neocortex.

One of the striking manifestations of neuronal population activity is that of rhythmic oscillations in the local field potential. It is thought that such oscillatory patterns, including phase-amplitude coupling (PAC) and inter-regional synchrony, may represent forms of local and long-range cortical computations, respectively. Although it has been speculated that these two oscillatory patterns are functionally related, and bind disparate cortical assemblies to one another at different timescales, there is little direct evidence to support this hypothesis. We have demonstrated recently that theta to high-gamma PAC and interlaminar phase coherence at theta frequencies can be generated in human cortical slices maintained in vitro. Here we show that not only do such oscillatory patterns exist within human temporal neocortex, but that the strength of one is related to the strength of the other. We demonstrate that at theta frequencies, metrics of temporal synchrony between superficial and deep cortical laminae (phase-dependent power correlations, and phase coherence) are correlated to the magnitude of intralaminar PAC between theta and high-gamma. Specifically, our results suggest that interlaminar communication within human temporal neocortex and local laminar excitability are linked to one another through a dependence mediated by theta oscillations. More generally, our results provide evidence for the hypothesis that theta oscillations may coordinate inter-areal excitability in the human brain.

Discrimination of cortical laminae using MEG

Typically MEG source reconstruction is used to estimate the distribution of current flow on a single anatomically derived cortical surface model. In this study we use two such models representing superficial and deep cortical laminae. We establish how well we can discriminate between these two different cortical layer models based on the same MEG data in the presence of different levels of co-registration noise, Signal-to-Noise Ratio (SNR) and cortical patch size. We demonstrate that it is possible to make a distinction between superficial and deep cortical laminae for levels of co-registration noise of less than 2mm translation and 2° rotation at SNR>11dB. We also show that an incorrect estimate of cortical patch size will tend to bias layer estimates. We then use a 3D printed head-cast (Troebinger et al., 2014) to achieve comparable levels of co-registration noise, in an auditory evoked response paradigm, and show that it is possible to discriminate between these cortical layer models in real data.

Cortical Depth Dependence of the Diffusion Anisotropy in the Human Cortical Gray Matter In Vivo

Diffusion tensor imaging (DTI) is typically used to study white matter fiber pathways, but may also be valuable to assess the microstructure of cortical gray matter. Although cortical diffusion anisotropy has previously been observed in vivo, its cortical depth dependence has mostly been examined in high-resolution ex vivo studies. This study thus aims to investigate the cortical depth dependence of the diffusion anisotropy in the human cortex in vivo on a clinical 3 T scanner. Specifically, a novel multishot constant-density spiral DTI technique with inherent correction of motion-induced phase errors was used to achieve a high spatial resolution (0.625×0.625×3 mm) and high spatial fidelity with no scan time penalty. The results show: (i) a diffusion anisotropy in the cortical gray matter, with a primarily radial diffusion orientation, as observed in previous ex vivo and in vivo studies, and (ii) a cortical depth dependence of the fractional anisotropy, with consistently higher values in the middle cortical lamina than in the deep and superficial cortical laminae, as observed in previous ex vivo studies. These results, which are consistent across subjects, demonstrate the feasibility of this technique for investigating the cortical depth dependence of the diffusion anisotropy in the human cortex in vivo.

Selective and Efficient Neural Coding of Communication Signals Depends on Early Acoustic and Social Environment

Previous research has shown that postnatal exposure to simple, synthetic sounds can affect the sound representation in the auditory cortex as reflected by changes in the tonotopic map or other relatively simple tuning properties, such as AM tuning. However, their functional implications for neural processing in the generation of ethologically-based perception remain unexplored. Here we examined the effects of noise-rearing and social isolation on the neural processing of communication sounds such as species-specific song, in the primary auditory cortex analog of adult zebra finches. Our electrophysiological recordings reveal that neural tuning to simple frequency-based synthetic sounds is initially established in all the laminae independent of patterned acoustic experience; however, we provide the first evidence that early exposure to patterned sound statistics, such as those found in native sounds, is required for the subsequent emergence of neural selectivity for complex vocalizations and for shaping neural spiking precision in superficial and deep cortical laminae, and for creating efficient neural representations of song and a less redundant ensemble code in all the laminae. Our study also provides the first causal evidence for ‘sparse coding’, such that when the statistics of the stimuli were changed during rearing, as in noise-rearing, that the sparse or optimal representation for species-specific vocalizations disappeared. Taken together, these results imply that a layer-specific differential development of the auditory cortex requires patterned acoustic input, and a specialized and robust sensory representation of complex communication sounds in the auditory cortex requires a rich acoustic and social environment.

Laminar analysis of 7 T BOLD using an imposed spatial activation pattern in human V1

With sufficient image encoding, high-resolution fMRI studies are limited by the biological point-spread of the hemodynamic signal. The extent of this spread is determined by the local vascular distribution and by the spatial specificity of blood flow regulation, as well as by measurement parameters that (i) alter the relative sensitivity of the acquisition to activation-induced hemodynamic changes and (ii) determine the image contrast as a function of vessel size. In particular, large draining vessels on the cortical surface are a major contributor to both the BOLD signal change and to the spatial bias of the BOLD activation away from the site of neuronal activity. In this work, we introduce a laminar surface-based analysis method and study the relationship between spatial localization and activation strength as a function of laminar depth by acquiring 1mm isotropic, single-shot EPI at 7T and sampling the BOLD signal exclusively from the superficial, middle, or deep cortical laminae. We show that highly-accelerated EPI can limit image distortions to the point where a boundary-based registration algorithm accurately aligns the EPI data to the surface reconstruction. The spatial spread of the BOLD response tangential to the cortical surface was analyzed as a function of cortical depth using our surface-based analysis. Although sampling near the pial surface provided the highest signal strength, it also introduced the most spatial error. Thus, avoiding surface laminae improved spatial localization by about 40% at a cost of 36% in z-statistic, implying that optimal spatial resolution in functional imaging of the cortex can be achieved using anatomically-informed spatial sampling to avoid large pial vessels.

Negative Blood Oxygen Level Dependence in the Rat:A Model for Investigating the Role of Suppression in Neurovascular Coupling

Modern neuroimaging techniques rely on neurovascular coupling to show regions of increased brain activation. However, little is known of the neurovascular coupling relationships that exist for inhibitory signals. To address this issue directly we developed a preparation to investigate the signal sources of one of these proposed inhibitory neurovascular signals, the negative blood oxygen level-dependent (BOLD) response (NBR), in rat somatosensory cortex. We found a reliable NBR measured in rat somatosensory cortex in response to unilateral electrical whisker stimulation, which was located in deeper cortical layers relative to the positive BOLD response. Separate optical measurements (two-dimensional optical imaging spectroscopy and laser Doppler flowmetry) revealed that the NBR was a result of decreased blood volume and flow and increased levels of deoxyhemoglobin. Neural activity in the NBR region, measured by multichannel electrodes, varied considerably as a function of cortical depth. There was a decrease in neuronal activity in deep cortical laminae. After cessation of whisker stimulation there was a large increase in neural activity above baseline. Both the decrease in neuronal activity and increase above baseline after stimulation cessation correlated well with the simultaneous measurement of blood flow suggesting that the NBR is related to decreases in neural activity in deep cortical layers. Interestingly, the magnitude of the neural decrease was largest in regions showing stimulus-evoked positive BOLD responses. Since a similar type of neural suppression in surround regions was associated with a negative BOLD signal, the increased levels of suppression in positive BOLD regions could importantly moderate the size of the observed BOLD response.

Epileptiform EEG Spikes and Their Functional Significance

Field potentials detected in the space surrounding cellular elements of the nervous system are essential in the diagnosis of epileptic seizures. This article describes the elementary mechanisms underlying the generation of field potentials and the special functional conditions leading to epileptiform field potentials. Primary transmembranous currents generate secondary ional currents along the cell membranes in intra- and extracellular compartments. The portion of these currents that flows through the brain tissue to the cortical surface can be detected as field potentials. A high synchronization of these field potentials is needed to induce brain signals. Field potentials recorded during epileptic activity are based on alterations in neuronal membrane potentials. Paroxysmal depolarization shift has proved to be characteristic in the epileptiform activity of individual neurons. Epileptiform field potentials are generated in functionally different structures with different elementary mechanisms. In focal convulsive activity limited to the cortex, the surface potential does not necessarily reflect the bioelectrical events in deeper cortical laminae and can be interrupted in different ways. The discrepancy between superficial EEG potentials and neocortical output may be the basis for dissociation between EEG signals and clinical signs.

Concatenation underlies interactions between gamma and beta rhythms in neocortex

The neocortex generates rhythmic electrical activity over a frequency range covering many decades. Specific cognitive and motor states are associated with oscillations in discrete frequency bands within this range, but it is not known whether interactions and transitions between distinct frequencies are of functional importance. When coexpressed rhythms have frequencies that differ by a factor of two or more interactions can be seen in terms of phase synchronization. Larger frequency differences can result in interactions in the form of nesting of faster frequencies within slower ones by a process of amplitude modulation. It is not known how coexpressed rhythms, whose frequencies differ by less than a factor of two may interact. Here we show that two frequencies (gamma – 40 Hz and beta2 – 25 Hz), coexpressed in superficial and deep cortical laminae with low temporal interaction, can combine to generate a third frequency (beta1 – 15 Hz) showing strong temporal interaction. The process occurs via period concatenation, with basic rhythm-generating microcircuits underlying gamma and beta2 rhythms forming the building blocks of the beta1 rhythm by a process of addition. The mean ratio of adjacent frequency components was a constant – approximately the golden mean – which served to both minimize temporal interactions, and permit multiple transitions, between frequencies. The resulting temporal landscape may provide a framework for multiplexing – parallel information processing on multiple temporal scales.

Cortical neuronal densities and lamination in focal cortical dysplasia

Focal cortical dysplasia (FCD) is considered to represent a malformation due to abnormal cortical development (MCD) and is an important cause of focal epilepsy. The histopathological features include abnormal laminar architecture, the presence of hypertrophic and dysmorphic neurones in FCD type IIA and additional balloon cells in FCD type IIB. The events causing these sporadic lesions are unknown, but abnormal progenitor cell proliferation occurring late in corticogenesis has been proposed. FCD-like lesions have, however, also been described following a cerebral injury early in life. We carried out a stereological assessment on 15 cases of FCD on NeuN- and Nissl-stained sections from patients with a wide age range, and identified a significant reduction in the neuronal density in all cases in the region of dysplasia compared to the adjacent unaffected cortex (mean neuronal densities 19.2x10(3)/mm3 in the region of dysplasia; 42.8x10(3)/mm3 in the adjacent cortex). Relative differences in neuronal density and size in FCD cases between the superficial (layer I and II) and deep cortical laminae (layer V and VI) were similar to that observed in other pathologies including mild MCD, temporal neocortex adjacent to hippocampal sclerosis as well as in a non-epilepsy surgical control group. The lower overall neuronal densities observed in FCD may reflect neuropil expansion, a local failure of neuronal migration, proliferation or secondary neuronal loss. The preservation of relative differences in neuronal densities between cortical layers and laminar patterns of neurofilament staining in FCD would support the view that the temporal sequence of lamination is not affected.

Cerebral cortical neurons with activity linked to central neurogenic spontaneous and evoked elevations in cerebral blood flow

We recorded neurons in rat cerebral cortex with activity relating to the neurogenic elevations in regional cerebral blood flow (rCBF) coupled to stereotyped bursts of EEG activity, burst-cerebrovascular wave complexes, appearing spontaneously or evoked by electrical stimulation of rostral ventrolateral medulla (RVL) or fastigial nucleus (FN). Of 333 spontaneously active neurons only 15 (5%), in layers 5–6, consistently ( P < 0.05, chi-square) increased their activity during the earliest potential of the complex, ∼ 1.3 s before the rise of rCBF, and during the minutes-long elevation of rCBF elicited by 10 s of stimulation of RVL or FN. The results indicate the presence of a small population of neurons in deep cortical laminae whose activity correlates with neurogenic elevations of rCBF. These neurons may function to transduce afferent neuronal signals into vasodilation.

The mouse mutation reeler causes increased adhesion within a subpopulation of early postmitotic cortical neurons

Early postmitotic cortical neurons are mostly corticofugal projection neurons that take up positions in deep cortical laminae. Later postmitotic neurons are preferentially localized to superficial cortical laminae. In reeler mutant mice it appears that cortical laminar positions with respect to birthdate are reversed (Caviness, 1982). In a reanalysis of reeler lamination we found that early postmitotic cortical neurons labeled by embryonic day (E) 11-13 injections of a birthdate marker, or by early postnatal day (PND) 2 retrograde labeling through their output projections, appear to take up positions both in the superficial and deep cortex. Neurons born on E11 and E12 are more likely to be situated superficially in the reeler cortex and neurons born on E13 are more likely to be situated in the deep reeler cortex. Many corticofugal projection neurons in the deep (but not superficial) reeler cortex either die or retract their axons before PND 21. We hypothesize that the earliest postmitotic (E11-E12) of the early postmitotic reeler cortical neurons are overly adhesive and act as a barrier to later postmitotic migrating neurons. In vitro cortical aggregation cultures confirmed that early postmitotic (E12) reeler neurons are more adhesive than early postmitotic (E12) wild-type neurons or late postmitotic (E16) reeler or wild-type cortical neurons. We suggest that the moderate wild-type preferential adhesion of early postmitotic cortical neurons to each other helps deep and superficially fated lineages to form cortical laminae.

Analysis of synaptic inputs and targets of physiologically characterized neurons in rat frontal cortex: Combined in vivo intracellular recording and immunolabeling

Ultrastructural immunocytochemical identification of transmitters in afferent terminals and targets of individual physiologically characterized neurons is essential for understanding the complex circuitry within the mammalian neocortex. For this type of analysis, we examined the utility of combining in vivo intracellular recording and biocytin injections with silver intensified 1 nm immunogold labeling of GABA and the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH). These transmitters are found to local neurons and afferents known to prominently modulate the activity of pyramidal neurons in the neocortex. Individual neurons were physiologically characterized and filled with biocytin in the frontal cortex of anesthetized rats. The brains were then preserved by vascular perfusion with aldehydes. Single vibratome sections through the recording site were reacted (1) for immunoperoxidase detection of biocytin and (2) for immunogold labeling of GABA or TH. Dually labeled sections were processed for light microscopy or embedded in plastic for electron microscopy. The dense peroxidase product for biocytin was detected in pyramidal neurons. These were located in superficial as well as deep cortical laminae, and were readily distinguished from immunogold silver labeling. GABA labeled terminals formed symmetric synapses with larger biocytin filled dendrites, whereas the TH labeled terminals contacted distal dendrites and spines. Peroxidase labeling for biocytin also was seen in a few axon terminals forming synapses with unlabeled and with GABA immunoreactive dendrites. These results suggest that single pyramidal neurons of the rat frontal cortex receive dual input from both GABA and catecholamine terminals. Additionally, this study demonstrates the usefulness of silver enhancement of 1 nm colloidal gold prior to plastic embedding for electron microscopic detection of neurotransmitters within afferents and targets of neurons physiologically characterized in vivo.

Tactile activity in primate primary somatosensory cortex during active arm movements: cytoarchitectonic distribution

1. Cells were recorded in areas 3b and 1 of the primary somatosensory cortex (SI) of three monkeys during active arm movements. Successful reconstructions were made of 46 microelectrode penetrations, and 298 cells with tactile receptive fields (RFs) were located as to cytoarchitectonic area, lamina, or both. 2. Area 3b contained a greater proportion of cells with slowly adapting responses to tactile stimuli and fewer cells with deep modality inputs than did area 1. Area 3b also showed a greater level of movement-related modulation in tactile activity than area 1. Other cell properties were equally distributed in the two areas. 3. The distribution of cells with low-threshold tactile RFs that also responded to lateral stretch of the skin or to passive arm movements was skewed toward deeper laminae than for tactile cells that did not respond to those manipulations. 4. The variation of activity of tactile neurons during arm movements in different directions was weaker in the superficial laminae than in deeper cortical laminae. 5. Cells with only increases in activity during arm movements were preferentially but not exclusively located in middle and superficial layers. Cells with reciprocal responses were found mainly in laminae III and V, whereas cells with only decreases in activity were concentrated in lamina V. 6. Overall, active arm movements evoke directionally tuned tactile and "deep" activity in areas 3b and 1, in particular in the deeper cortical laminae that are the source of the descending output pathways from SI.

Quantitative radioautographic study of somatostatin receptors heterogeneity in the rat extrahypothalamic brain

The possible heterogeneity of extrahypothalamic somatostatin receptors was studied in rat brain by quantitative radioautography. The respective distribution and relative proportion of two somatostatin receptor sub-types (SS1 and SS2) were assessed by using two radioligands, the non-selective probe [ 125I]Tyr 3- d-Trp 8-somatostatin 14 and the SS1 selective analogue [ 125I]Tyr 3-SMS 201–995. For both ligands, adjacent brain sections were processed in the presence of micromolar concentrations of either a non-descriminative competitor (somatostatin 14) or SSl-selective analogue (SMS 201–995). The comparative analysis of the specific binding remaining in the presence of each non-radioactive competitor permitted a semi-quantitative analysis of the proportion of SS1 and SS2 receptor sub-types in each brain region examined. Data obtained correlate well with homogenate binding results reported previously [Reubi J. C. (1984) Neurosci. Lett. 49, 259–263]. Although the distribution patterns obtained with both radioligands were similar, [ 125I]Tyr 3-SMS 201–995 labelled only a fraction of [ 125I]Tyr 0- d-Trp 8-somatostatin 14-labelled sites in certain brain regions. For example, both superficial and deep cortical laminae, as well as the basolateral amygdaloid nucleus and CA1 hippocampal area exhibited different binding densities with [ 125I]Tyr 0- d-Trp 8-somatostatin 14 depending on the competitor used in the assay (somatostatin 14 or SMS 201–995). On the other hand, [ 125I]Tyr 3-SMS 201–995 binding was eliminated in an identical fashion by either competitor in these very same brain areas. This suggests the existence of SS1 and SS2 somatostatin receptor sub-types in these regions. In all other brain areas examined, somatostatin receptor sites are apparently of the SS1 sub-type. The heterogeneity of somatostatin receptors observed in certain regions may have relevance for the various biological effects induced by somatostatin in the central nervous system.

Projections from visual cortical area 19, the posterior medial lateral suprasylvian area and the lateral posterior-pulvinar complex of the thalamus to areas 17 and 18 in young kittens

Retrogradely transported horseradish peroxidase (HRP) or HRP conjugated to wheat germ agglutinin was used to demonstrate projections from area 19, the posterior medial lateral suprasylvian area (PMLS) and the lateral posterior-pulvinar complex (LP-PC) of the thalamus to areas 17 and 18 of the visual cortex in young kittens. Areas 17 and 18 in kittens, as in adult cats, receive association fibres from cells lying mainly in deep cortical laminae in area 19 and PMLS, and projections from the LP-PC of the thalamus.

Degeneration of thalamic neurons in "Purkinje cell degeneration" mutant mice. I. Distribution of neuron loss.

The Purkinje cell degeneration (pcd) mutation of the mouse is an autosomal recessive allele which previous studies have shown to be the cause of rapid degeneration of nearly all cerebellar Purkinje cells between 18 and 30 postnatal days of age (P18-P30), and slowly developing, progressive losses of retinal photoreceptor cells and mitral cells of the olfactory bulb. Through examination of serial frozen sections alternately stained for Nissl substance and for degenerating neuronal processes, we have found that discrete populations of thalamic neurons degenerate rapidly between P50 and P60. Severely affected nuclei, in which a majority of neurons degenerate, include the central division of the mediodorsal nucleus, the ventral medial geniculate, posterior, posterior ventromedial, and submedial nuclei, and those portions of the ventrolateral and posteromedial nuclei which immediately surround the medial division of the ventrobasal complex. More subtle cell losses occur during the same time period in restricted portions of the lateral ventrobasal, dorsal lateral geniculate, and lateral posterior nuclei, but even at P180 these nuclei are not markedly atrophic. No common denominator among target cell populations has been established. The pcd allele affects a diverse assortment of specific relay nuclei; degeneration has not been recognized in thalamic nuclei characterized primarily or exclusively by subcortical projections or by cortical projections directed relatively selectively to superficial or deep cortical laminae. The neuronal degenerations in the thalamus are not precipitated by prior or concurrent degeneration of cortical targets or afferent sources, though striking transneuronal changes, including cell death, do develop following thalamic neuronal degeneration in this mutant. No previously described murine mutant phenotype includes the rapid degeneration of highly restricted neuronal populations beginning at these relatively advanced ages.