The thalamocortical projection to rodent somatosensory ("barrell") cortex is highly ordered in both the radial and the tangential dimensions. During a brief period of postnatal development, thalamocortical axons establish two tiers of terminations, in the deep layers and in layer IV, and form whisker-specific clusters within layer IV; however, little is known about the cues that guide them to their appropriate radial and tangential positions. To gain insight into potential mechanisms underlying this process, we studied the development of thalamocortical termination patterns in mouse barrel cortex at high spatial resolution. Developing thalamocortical axons were labeled in fixed slices with the lipophilic carbocyanine dye Dil and imaged with a laser scanning confocal microscope. On the day of birth (postnatal day 0, P0) axons coursed through layers VI and V, with little or no branching. By P2 the lower tier of terminations, at the border of layers VI and V, was clearly identifiable. Below this tier axons coursed obliquely or tangentially, forming a dense meshwork of intersecting fibers, but with no apparent branching. By P4 the upper tier of terminations, in layer IV, was clearly recognizable, and consisted of periodic, dense clusters of terminal arborizations. In marked contrast to the oblique and apparently disorderly course followed by axons in layer VI and lower layer V, axons in upper layer V heading toward the upper tier were organized in loose bundles running radially, suggesting that axons destined to terminate in a particular layer IV barrel had already reached their appropriate tangential coordinates within the lower tier. Thus, the pattern of thalamocortical terminations in layer IV seems to be projected from the deep tier of terminations, and does not develop from an initially profuse arborization pattern through pruning of inappropriate branches.

Somatosensory thalamus and cortex in rodents contain topological representations of the facial whisker pad. The thalamic representation of a single whisker ("barreloid") is presumed to project exclusively to the cortical representation ("barrel") of the same whisker; however, it was not known when this correspondence is established during early development, nor how precise the thalamocortical projection is at birth, before formation of barrels and barreloids. To answer these questions, we retrogradely labeled thalamocortical projection neurons in fixed brain slices from 0-8 d old (P0-P8) mice, by placing paired deposits of two fluorescent dyes in adjacent barrels or (before barrel formation) in adjacent loci in upper cortical layers. At all ages studied, a negligible fraction of the retrogradely labeled cells was double labeled, implying that branches of single thalamocortical axons never extended within layer IV over an area wider than a single barrel. In P0 preparations, 70% of paired dye deposits placed 75-200 microns apart resulted in statistically significant segregation of labeled cell clusters in the thalamus. Quantitative analysis indicated that on P0 about 70% of thalamocortical axons were within 1.3 presumptive barrel diameters from their topologically precise target. In P4-P8 preparations, the great majority of thalamic cells retrogradely labeled from a single barrel were found in a single barreloid, implying a 1:1 projection of barreloids to barrels. The postnatal increase in topological precision was reproduced by a computer simulation, which assumed that many aberrant axons corrected their initial targeting error by extending terminal arborizations asymmetrically, towards the center of their appropriate barrel.

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Mitochondria provide most of the energy for brain cells by the process of oxidative phosphorylation. Mitochondrial abnormalities and deficiencies in oxidative phosphorylation have been reported in individuals with schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) in transcriptomic, proteomic, and metabolomic studies. Several mutations in mitochondrial DNA (mtDNA) sequence have been reported in SZ and BD patients.

Dorsolateral prefrontal cortex (DLPFC) from a cohort of 77 SZ, BD, and MDD subjects and age-matched controls (C) was studied for mtDNA sequence variations and heteroplasmy levels using Affymetrix mtDNA resequencing arrays. Heteroplasmy levels by microarray were compared to levels obtained with SNaPshot and allele specific real-time PCR. This study examined the association between brain pH and mtDNA alleles. The microarray resequencing of mtDNA was 100% concordant with conventional sequencing results for 103 mtDNA variants. The rate of synonymous base pair substitutions in the coding regions of the mtDNA genome was 22% higher (p = 0.0017) in DLPFC of individuals with SZ compared to controls. The association of brain pH and super haplogroup (U, K, UK) was significant (p = 0.004) and independent of postmortem interval time.

Focusing on haplogroup and individual susceptibility factors in psychiatric disorders by considering mtDNA variants may lead to innovative treatments to improve mitochondrial health and brain function.