Search

We asked whether the physiological and morphologic properties of hypoglossal motor neurons (CNXII MNs) that innervate protruder or retractor tongue muscles are disrupted in neonatalLgDelmice that carry a heterozygous deletion parallel to that associated with DiGeorge/22q11.2 deletion syndrome (22q11.2DS). Disrupted coordination of tongue movement inLgDelmouse pups may contribute to suckling, feeding, and swallowing (S/F/S) disruptions that parallel pediatric dysphagia in infants and toddlers with 22q11.2DS. Using anin vitrorhythmically active medullary slice preparation, we found spontaneous firing as well as IPSC frequency differed significantly in neonatalLgDelversus wild-type (WT) protruder and retractor CNXII MNs that were identified by retrograde tracing from their target muscles. In response to respiration-related activity, initiation and decay of transiently increased firing in WT protruder MNs is delayed inLgDel, accompanied by altered excitatory/inhibitory (E/I) balance. In addition,LgDelretractor MNs have a transient increase in firing with diminished IPSC frequency that is not seen in WT. There were no significant differences in cell body volume of either XII class in WT andLgDel. Sholl analysis showed the total numbers of dendritic intersections (at 50- and 90-μm radii from the cell soma) were significantly greater forLgDelversus WT retractor MNs. Thus, the physiological, synaptic and cellular properties of distinct classes of CNXII MNs that coordinate tongue movement in neonatal WT mice are altered inLgDel. Such changes could contribute to sub-optimal coordination of S/F/S that underlies pediatric dysphagia in 22q11.2DS.

We characterized intrinsic and extrinsic specification of progenitors in the lateral and medial ganglionic eminences (LGE and MGE). We identified seven genes whose expression is enriched or restricted in either the LGE [biregional cell adhesion molecule-related/downregulated by oncogenes binding protein (Boc), Frizzled homolog 8 (Fzd8),Ankrd43(ankyrin repeat domain-containing protein 43), andIkzf1(Ikaros family zinc finger 1)] or MGE [Map3k12 binding inhibitory protein 1 (Mbip); zinc-finger, SWIM domain containing 5 (Zswim5); andAdamts5[a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 5]].Boc,Fzd8,Mbip, andZswim5are apparently expressed in LGE or MGE progenitors, whereas the remaining three are seen in the postmitotic mantle zone. Relative expression levels are altered and regional distinctions are lost for each gene in LGE or MGE cells propagated as neurospheres, indicating that these newly identified molecular characteristics of LGE or MGE progenitors depend on forebrain signals not available in the neurosphere assay. Analyses ofPax6Sey/Sey,Shh−/−, andGli3XtJ/XtJmutants suggests that LGE and MGE progenitor identity does not rely exclusively on previously established forebrain-intrinsic patterning mechanisms. Among a limited number of additional potential patterning mechanisms, we found that extrinsic signals from the frontonasal mesenchyme are essential for Shh- and Fgf8-dependent regulation of LGE and MGE genes. Thus, extrinsic and intrinsic forebrain patterning mechanisms cooperate to establish LGE and MGE progenitor identity, and presumably their capacities to generate distinct classes of neuronal progeny.

We have analyzed blood vessel distribution in the primary and secondary visual cortices of the squirrel monkey in relation to cortical modules, laminae, and cytoarchitectonic areas. Measurements of microvessel length in tangential sections through the primary visual cortex showed that blobs are more richly vascularized than intervening cortical regions. Thus, the mean total length of microvessel profiles per unit was 42% greater within these cortical modules than within adjacent (interblob) areas. Total microvessel length per unit area in another class of module, the stripes in the secondary visual cortex, was 27% greater than in interstripe regions. Microvessel distribution also varied systematically from layer to layer in the primary visual cortex, being greatest in lamina IVc. Finally, the overall microvessel length per unit area in sections of the primary visual cortex was 26% greater than that in the secondary visual cortex. These observations indicate that the modular, laminar, and regional organization of the primate visual cortex is reflected in the underlying distribution of cortical microvessels. These vascular patterns should be discernable in living animals with vascular contrast agents and appropriate imaging techniques.

We have undertaken a quantitative analysis of the mouse olfactory bulb to address several major questions concerning the development of neural circuitry in the postnatal mammalian brain. These are: (1) To what degree are new elements and circuits added during maturation? (2) How long do such processes go on? and (3) Does postnatal development involve a net addition of circuits and their constituent elements, or is there elimination of some portion of an initial surfeit? Using male mice of known age, weight, and length, we measured the overall size of the bulb, the numbers of processing units (glomeruli) within the bulb, the extent and complexity of postsynaptic dendrites within the glomeruli, and the number of synapses in different regions of the bulb. Between birth and the time mice reach sexual maturity at 6–7 weeks of age, the bulb increases in size by a factor of 8, the number of glomeruli by a factor of 4–5, the length of mitral cell dendritic branches by a factor of 11, and the number of glomerular and extraglomerular synapses by factors of 90 and 170, respectively. Each of these parameters increases steadily from birth, in concert with the enlargement of the olfactory mucosa, the overall growth of the brain, and indeed, of the entire animal. We found no evidence of an initial surfeit of processing units, dendritic branches, or synapses. Further elaboration of neural circuitry by each of these measures is also apparent from the time of sexual maturity until the animals reach their full adult size at about 10–12 weeks of age. The developmental strategy in this part of the mouse brain evidently involves prolonged construction that persists until the growth of the body is complete. This ongoing elaboration of neural circuitry in the postnatal mammalian brain may be relevant to understanding a number of unexplained developmental phenomena, including critical periods, the ability of the juvenile brain to recover from injuries that would cause severe and permanent deficits in older animals, and the special ability of the maturing brain to encode large amounts of new information.

The extent to which the development of a normal laminated lateral geniculate nucleus depends upon retinal afferents has been studied in normal and albino ferrets and in mink. Removal of all retinal afferents before they invade the nucleus (28 days in utero) or before they establish distinct monocular terminal fields (newborn, approximately 41 days post-conception) produces a nucleus that is smaller than normal and poorly separated from the adjacent perigeniculate and medial interlaminar nuclei. However, the nucleus is wedge-shaped, resembling a normal adult nucleus, in which a broad medial binocular segment is distinguishable from a narrower lateral monocular segment. There is a normal mediolateral gradient of cell sizes and some signs of a laminar differentiation, cells next to the optic tract being morphologically distinguishable from cells near the optic radiation, but no cell-free interlaminar zones are formed. The development of a monocularly innervated nucleus depends on the size of the surviving retinal input. In normally pigmented ferrets or mink the crossed retinofugal component is larger than the uncrossed component. In the monocular animals one sees essentially a monocular set of geniculate layers on each side, with an appropriate asymmetry. Each nucleus can be regarded as representing the survival of those layers which would have been innervated by the good eye, together with some additional geniculate territory that appears to be added to the surviving layers as retinogeniculate axons occupy territory normally innervated by the other eye. The crossed component of an albino ferret is abnormally large and the monocularly innervated contralateral nucleus is almost like that of a normal albino. There is a full complement of geniculate layers and interlaminar zones, which appears to develop without any binocular interactions. The ipsilateral retinogeniculate component of albinos is extremely small. In the monocular albino animals it forms discontinuous terminal patches, leaving sectors of the poorly differentiated nucleus uninnervated. These results show that in geniculate development there is a limited interaction between the two sets of retinal afferents. Each set plays a well defined and distinctive role, and one can replace the other to a limited extent only.