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The thalamic reticular nucleus (TRN) is a unique brain structure at the interface between the thalamus and the cortex. Because the TRN receives bottom-up sensory input and top-down cortical input, it could serve as an integration hub for sensory and cognitive signals. Functional evidence supports broad roles for the TRN in arousal, attention, and sensory selection. How specific circuits connecting the TRN with sensory thalamic structures implement these functions is not known. The structural organization and function of the TRN is particularly interesting in the context of highly organized sensory systems, such as the primate visual system, where neurons in the retina and dorsal lateral geniculate nucleus of the thalamus (dLGN) are morphologically and physiologically distinct and also specialized for processing particular features of the visual environment. To gain insight into the functional relationship between the visual sector of the TRN and the dLGN, we reconstructed a large number of TRN neurons that were retrogradely labeled following injections of rabies virus expressing enhanced green fluorescent protein (EGFP) into the dLGN. An independent cluster analysis, based on 10 morphological metrics measured for each reconstructed neuron, revealed three clusters of TRN neurons that differed in cell body shape and size, dendritic arborization patterns, and medial-lateral position within the TRN. TRN dendritic and axonal morphologies are inconsistent with visual stream-specific projections to the dLGN. Instead, TRN neuronal organization could facilitate transmission of global arousal and/or cognitive signals to the dLGN with retinotopic precision that preserves specialized processing of foveal versus peripheral visual information.

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Purpose Disruption of proteostasis is a key event in many neurodegenerative diseases. Heat shock proteins (HSPs) participate in multiple functions associated with intracellular transport and proteostasis. We evaluated the effect of augmented HSP70 expression in mutant photoreceptors of mouse retinal degeneration models to test the hypothesis that failure to sustain HSP70 expression contributes to photoreceptor cell death. Methods We examined HSP70 expression in retinas of wild-type and mutant mice by RNA and protein analysis. A transgenic mouse line, TgCrx-Hspa1a-Flag , was generated to express FLAG-tagged full-length HSP70 protein under control of a 2.3 kb mouse Crx promoter. This line was crossed to three distinct retinal degeneration mouse models. Retinal structure and function were evaluated by histology, immunohistochemistry, and electroretinography. Results In seven different mouse models of retinal degeneration, we detected transient elevation of endogenous HSP70 expression at early stages, followed by a dramatic reduction as cell death ensues, suggesting an initial adaptive response to cellular stress. Augmented expression of HSP70 in RHOT17M mice, in which mutant rhodopsin is misfolded, marginally improved photoreceptor survival, whereas elevated HSP70 led to more severe retinal degeneration in rd10 mutants that produce a partially functional PDE6B. In Rpgrip1 − / − mice that display a ciliary defect, higher HSP70 had no impact on photoreceptor survival or function. Conclusions HSP70 overexpression has divergent effects in photoreceptors determined, at least in part, by the nature of the mutant protein each model carries. Additional investigations on HSP pathways and associated chaperone networks in photoreceptors are needed before designing therapeutic strategies targeting proteostasis.

I would like to address some of the issues raised in Dr Kuhn's letter in response to my article. 1 I appreciate his letter and the important discussions it will generate.Dr Kuhn and I agree on several things: that the physicians we recruit into ophthalmology should be competent and empathetic, that racial discrimination is harmful and should be ended, and that we should support underrepresented minority (URM) applicants to ophthalmology. Where we seem to differ is the method to accomplish these goals.Dr Kuhn argues that the way to defeat discrimination is to ignore race and ethnicity entirely and hope that inequality goes away. This "color-blind" mentality does not allow us to see and actively address inequalities within our system. As our study and many other studies have shown, ophthalmology as a field is less diverse than other specialties, and we should ask ourselves why. 2 I emphatically reject Dr Kuhn's line of reasoning that implies that this discrepancy is because URM candidates are less qualified or competent than other applicants. There are qualified applicants from underrepresented backgrounds graduating from medical school, but the numbers show they are disproportionately pursuing specialties other than ophthalmology. Furthermore, if our metrics for determining who is qualified for a residency or faculty position result in a workforce that excludes URM physicians, we have to evaluate whether those metrics are objective or necessary. For example, do traditional metrics such as a high board score or attending a prestigious medical school truly determine whether one will be a competent and empathetic physician?The Association of American Medical Colleges advocates for a holistic, mission-driven, diversity-oriented evaluation of residency applicants that considers their experiences, attributes, competencies, and academic metrics. 3 The holistic review process is not a quota system, nor does it lower standardsdit expands them. 3 Race and ethnicity are among the many factors that shape our lives, perspectives, and relationships with coworkers, patients, and the communities in which we practice. 4 For myself, like many other physicians from underrepresented backgrounds, my culture deeply influences my career goals and, I believe, adds value to our field. Indeed, studies show that diversity improves learning