Effects of Donepezil on Behavioral Manifestations of Thalamic Infarction: A Single-Case Observation

Objective: To examine the effect of donepezil for the treatment of cognitive and behavioral disorders associated with thalamic lesions in a 45-year-old male who suffered an infarct in the left thalamus. Background: Recent studies suggest that donepezil may improve executive functions impairments due to subcortical ischemic lesions. Method: The effects of donepezil were analyzed in a single-case of thalamic infarction with cognitive and behavioral alterations in an open label study. Results: Significant behavioral modifications related to improved performances in executive functions were observed with the treatment. Conclusion: The results suggest that donepezil may have significant effect on executive functions that can alter behavioral outcomes after thalamic infarctions

Sonic hedgehog signaling in the development of the mouse hypothalamus

The expression pattern of Sonic Hedgehog (Shh) in the developing hypothalamus changes over time. Shh is initially expressed in the prechordal mesoderm and later in the hypothalamic neuroepithelium-- first medially, and then in two off-medial domains. This dynamic expression suggests that Shh might regulate several aspects of hypothalamic development. To gain insight into them, lineage tracing, (conditional) gene inactivation in mouse, in ovo loss- and gain-of-function approaches in chick and analysis of Shh expression regulation have been employed. We will focus on mouse studies and refer to chick and fish when appropriate to clarify. These studies show that Shh-expressing neuroepithelial cells serve as a signaling center for neighboring precursors, and give rise to most of the basal hypothalamus (tuberal and mammillary regions). Shh signaling is initially essential for hypothalamic induction. Later, Shh signaling from the neuroepithelium controls specification of the lateral hypothalamic area and growth-patterning coordination in the basal hypothalamus. To further elucidate the role of Shh in hypothalamic development, it will be essential to understand how Shh regulates the downstream Gli transcription factors

Mouse thalamic differentiation: Gli-dependent pattern and Gli-independent prepattern

Sonic hedgehog (Shh) is essential for ventral neural tube development. The Gli transcription factors act downstream Shh—while Gli2 is the major activator (GliA), Gli3 acts primarily as a repressor (GliR). Remarkably, the thalamus, a dorsal region, develops close to the mid-diencephalic organizer, a unique dorsal Shh source. This lends complexity to the Shh-Gli interactions, suggesting the presence of a dorsal Gli activator elsewhere found only ventrally, and making the dissection of thalamic Gli functions particularly interesting. A current model postulates reciprocal antagonism of Shh and Gli3 in dorsal brain regions. To approach the thalamic role of Gli factors we first analyzed Gli2 and Gli3 mutants. In Gli2 mutants, the thalamus is small and poorly differentiated with the exception of the medial and intralaminar nuclei which, in contrast, are specifically and severely affected by Gli3 inactivation. Gbx2 expression is very reduced in the Gli3 mutant. Most thalamic nuclei are present in both mutants, although incompletely differentiated. The ventral posterior group, revealed by marker Hes1, is present in both mutants and extends axons to the telencephalon.To test the Gli3/Shh interaction we used a novel mutant lacking Gli3 and neuroepithelial Shh. The n-Shh/Gli3 thalamus is very large and very poorly differentiated except for a broad domain of Gbx2-Lhx2-Calb2 expression. In utero electroporation experiments on wildtype embryos suggest that a stage-specific factor acting early is responsible for this prepattern.We show that, in the thalamus, GliA acts downstream Shh to specify thalamic nuclei except the medial and intralaminar. Gli3A can partially substitute for Gli2A in the Gli2 mutant. GliR is essential for specification and growth of the medial and intralaminar nuclei, contributes to the specification of other thalamic nuclei and reduces thalamic size. Finally, GliA (from neuroepithelial Shh signaling) and GliR are not reciprocally antagonic in the thalam

Lhx5 controls mamillary differentiation in the developing hypothalamus of the mouse

Acquisition of specific neuronal identity by individual brain nuclei is a key step in brain development. However, how the mechanisms that confer neuronal identity are integrated with upstream regional specification networks is still mysterious. Expression of Sonic hedgehog (Shh), is required for hypothalamic specification and is later downregulated by Tbx3 to allow for the differentiation of the tubero-mamillary region. In this region, the mamillary body (MBO), is a large neuronal aggregate essential for memory formation. To clarify how MBO identity is acquired after regional specification, we investigated Lhx5, a transcription factor with restricted MBO expression. We first generated a hypomorph allele of Lhx5—in homozygotes, the MBO disappears after initial specification. Intriguingly, in these mutants, Tbx3 was downregulated and the Shh expression domain abnormally extended. Microarray analysis and chromatin immunoprecipitation indicated that Lhx5 appears to be involved in Shh downregulation through Tbx3 and activates several MBO-specific regulator and effector genes. Finally, by tracing the caudal hypothalamic cell lineage we show that, in the Lhx5 mutant, at least some MBO cells are present but lack characteristic marker expression. Our work shows how the Lhx5 locus contributes to integrate regional specification pathways with downstream acquisition of neuronal identity in the MBO

LIM homeobox protein 5 (Lhx5) is essential for mamillary body development

The mamillary body (MM) is a group of hypothalamic nuclei related to memory and spatial navigation that interconnects hippocampal, thalamic, and tegmental regions. Here we demonstrate that Lhx5, a LIM-HD domain transcription factor expressed early in the developing posterior hypothalamus, is required for the generation of the MM and its derived tracts. The MM markers Foxb1, Sim2 and Lhx1 are absent in Lhx5 knock-out mice from early embryonic stages, suggesting abnormal specification of this region. This was supported by the absence of Nkx2.1 and expansion of Shh in the prospective mamillary area. Interestingly, we also found an ectopic domain expressing Lhx2 and Lhx9 along the anterio-posterior hypothalamic axis. Our results suggest that Lhx5 controls early aspects of hypothalamic development by regulating gene expression and cellular specification in the prospective MM