Research ReportStriatal projections from the rat lateral posterior thalamic nucleus
Introduction
The rat lateral posterior thalamic nucleus (LP) plays a key role in circuitry for directed attention and its dysfunctional counterpart, contralateral neglect. Nucleus LP has reciprocal connections with the medial agranular (AGm or Fr2) and posterior parietal (PPC) cortices (Reep et al., 1994, Reep and Corwin, 1999, Sukekawa, 1988), which are the main cortical areas implicated in neglect in rats. Furthermore, LP projects to the dorsocentral striatum (DCS), a site of convergence for corticostriatal projections from AGm and PPC (Cheatwood et al., 2005, Cheatwood et al., 2003, Erro et al., 2002). The projection from LP to DCS is the focus of the present study, due to the critical role of DCS as a nodal point necessary for recovery from neglect.
Following unilateral lesions of AGm or PPC, behavioral manifestations of neglect in rodents are similar to those found in humans, and include: contralesional neglect of visual, tactile, and auditory stimuli, extinction, allesthesia/allokinesia, and disorders of spatial processing (Corwin and Reep, 1998, King and Corwin, 1992, King and Corwin, 1993). These signs of neglect in rats with cortical lesions are significantly improved temporarily following systemic administration of apomorphine (a dopamine receptor agonist) (Corwin et al., 1986, King and Corwin, 1990), and spiroperidol (a dopamine receptor antagonist) can reinstate neglect (Corwin et al., 1986). While dopamine agonist treatment was effective, the site of action for these therapeutic effects was unknown. However, we strongly suspected that DCS might play this role, because it is the major striatal target of projections from AGm and PPC (Reep et al., 2003, Reep and Corwin, 1999). In rats with neglect produced by cortical lesions, direct cannulation of apomorphine into DCS, but not a laterally adjacent area, produces virtually identical effects to those seen following systemic injections (Van Vleet et al., 2003). These findings indicate that the integrity of the DCS is a crucial link in the circuitry for directed attention, and may be essential for recovery from neglect to occur.
Behavioral and anatomical findings in the rodent model further support the role of DCS in neglect and behavioral recovery. We have found that unilateral axon-sparing DCS lesions produce severe neglect which does not recover spontaneously, even after 96 days of testing (Van Vleet et al., 2000, Van Vleet et al., 2002). Further, systemic administration of apomorphine does not produce recovery from neglect in DCS operates. The ineffectiveness of apomorphine and the failure of DCS operates to demonstrate spontaneous recovery, suggest that DCS may be the site that mediates spontaneous recovery from neglect as well as the therapeutic effects of apomorphine. These studies have provided a foundation for our current investigations of the role of induced corticostriatal and thalamostriatal synaptic plasticity in recovery from neglect (Brenneman et al., 2007, Reep et al., 2004).
The central role of DCS in neglect and recovery points to the importance of understanding its neuronal connections and how they interact. Key among these are cortical and thalamic projections, which represent the dominant excitatory inputs to all regions of the striatum and contribute approximately equal numbers of synapses (see Kincaid et al., 1998). Neuronal inputs from AGm and PPC represent a principal means by which spatial information reaches DCS and converges with inputs from other cortical areas, including visual association area Oc2M, orbital, and motor cortex (Cheatwood et al., 2003, Reep et al., 2003). These cortical areas are also linked by corticocortical connections (Reep et al., 1994, Reep et al., 1996, Reep et al., 1990, Reep and Corwin, 1999, Vandevelde et al., 1996). In addition, several of the thalamic nuclei that project to these cortical areas also project to DCS (Cheatwood et al., 2005, Cheatwood et al., 2003, Erro et al., 2002). Thus, as has been hypothesized in humans, we have evidence that DCS and these cortical and thalamic regions represent a cortical-subcortical network for directed attention and in which damage, results in neglect (Cheatwood et al., 2003, Reep et al., 2003, Reep et al., 2004). Based on these functional and anatomical properties, we have suggested that DCS represents an associative region of the striatum, distinct from the sensorimotor and limbic striatal regions (Reep et al., 2003, Reep et al., 2004).
Based on three lines of evidence, nucleus LP, the rodent homologue of the pulvinar, appears to play a pivotal role in the circuitry for directed attention and neglect. First, LP has extensive connections with AGm and PPC as well as with visual areas Oc1, Oc2L, Oc2M, (Reep et al., 1994, Reep et al., 1990, Sefton et al., 2004). It is unknown whether single LP neurons have axons that branch to innervate these areas, or if these cortical projections originate in separate populations of LP neurons. Our preliminary findings suggest that separate but neighboring populations of LP neurons project to AGm and PPC (Reep et al., 1994, Reep and Corwin, 1999). Second, LP has reciprocal connections with the superior colliculus (see Sefton et al., 2004), a major center for directed motor activation. Third, LP projects to DCS and may overlap with similarly organized projections from cortical areas PPC and Oc2M (Cheatwood et al., 2005). Whether this is the case has implications for how information is parceled and processed in DCS.
The present study was undertaken to map the projections from LP to striatum, with a focus on DCS. We were particularly interested in discovering whether the projection from LP to DCS originated solely from far medial LP, as suggested by prior retrograde tracing (Cheatwood et al., 2003).
Section snippets
Injection sites
BDA sections with the densest injection site were selected for each case and the locations of the injection sites were determined by the use of corresponding CV sections. Based on the locations of the injection sites, cases were divided into 7 groups with injection centers focused in the following thalamic nuclei; medial LPMR (cases 239, 297, 327, 238), central/lateral LPMR (cases 328, 295, 240, 235, 242), lateral LPLR (case 326), lateral LDDM (cases 354, 319), medial LDVL (case 252), CL (case
Discussion
The most significant finding of the present study is that the CPu receives inputs from LP and several thalamic nuclei contiguous to LP, but the strongest inputs to the central DCS originate in the far medial portion of LPMR. In contrast, the central region of LPMR projects to the dorsal region of DCS and the lateral portion of LPMR does not project to DCS. Other thalamic nuclei surrounding LPMR project to CPu but have no projection to DCS. These findings suggest that the far medial portion of
Experimental procedures
A total of 16 male Long-Evans Hooded rats were used in this study. All animal procedures were carried out in accordance with the United States Public Health Service Guide for the Care and Use of Laboratory Animals, and with IACUC approval at the University of Florida. Animals were anesthetized with an intraperitoneal injection of a ketamine/xylazine cocktail (90 mg/kg:10 mg/kg) and placed in a stereotaxic device. A hole was then drilled in the skull at the selected locations. The anterograde
Acknowledgments
We thank Maggie Stoll, Billy Conte, Lori Lazar, and Harumi Kamishina for their technical contributions. This study was supported by NIMH grant MH60399.
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