Afferent projections of the subthalamic nucleus in the rat: emphasis on bilateral and interhemispheric connections

Abstract

The subthalamic nucleus (STN) is important for normal movement as well as in movement disorders. The STN is a target nuclei in patients with advanced Parkinson's disease (PD). Deep brain stimulation (DBS) is a standard surgical treatment for PD. Although DBS results in a significant reduction in motor disability, several negative side effects have been reported. Thus, to understand the side effects of DBS the connection of the STN should be well known. Therefore, the present study aims to reexamine the STN with an emphasis on poorly-or undocumented connections. Furthermore, the bilateral and interhemispheric connections of the STN are evaluated. Fifteen male albino rats received injections of Fluoro-Gold retrograde and biotinylated dextran amine anterograde tracers into the STN. Following a 7-10 day survival period, the animals were processed according to the relevant protocol for each tracer. The present study demonstrates ipsilateral connections of the STN with cortical regions (i.e., infralimbic, cingulate, frontal, piriform, primary motor, primary sensory, insular and retrosplenial cortices), the endopiriform nucleus, basal ganglia related structures (i.e., caudate putamen, globus pallidus, ventral pallidum, nucleus accumbens, claustrum and substantia innominata) and the deep cerebellar nuclei (i.e., lateral, anterior interposed). Bilateral connections of the STN were observed with limbic (amygdala, bed nucleus of stria terminalis), hypothalamic (ventromedial, posterior, anterior, lateral and mammillary) thalamic (thalamic reticular nucleus), epithalamic (habenular nucleus), and brainstem structures (superior colliculus, substantia nigra, spinal nucleus of the trigeminal nerve, red nucleus, dorsal raphe nucleus, pedunculopontine tegmental nuclei). Interhemispheric connections between left and right STN were also observed. The present study fills important gaps in connectivity of the STN. In particular, we report STN connectivity with cortical areas (i.e., piriform, endopiriform and insular), claustrum, hypothalamic, thalamic reticular, cerebellar, habenular, trigeminal, red, cuneate and gracile nuclei and substantia innominate. These connections, which have not been previously described or poorly described, provide new routes that can alter the conceptual architecture of the basal ganglia circuitry and may modify our view of the functional identity of the STN.

Deep Brain Stimulation of the Subthalamic Nucleus Modulates Reward-Related Behavior: A Systematic Review

“…This division receives inputs from the medial prefrontal and anterior cingulate cortices and projects to the ventral pallidum and the nucleus accumbens (Cavdar et al, 2018;Emmi et al, 2020). Limbic functions of the STN involve reward encoding and sensory integration to drive appropriate emotional states (Drapier et al, 2008;Lardeux et al, 2009;Eitan et al, 2013;Zenon et al, 2016).…”

“…Even if it is current spread to STN subterritories and adjacent structures, and not modulation of the motor STN per se that drives reward-seeking deficits, this still does not explain the precise mechanisms underlying these deficits. For example, the reward-related effects could also be due to antidromic activation of afferent structures such as the prefrontal cortex (Irmen et al, 2020), or to modulation of downstream structures such as ventral pallidum or nucleus accumbens (Hahn et al, 2008;Cavdar et al, 2018). Likewise, STN-DBS modulates dopamine tone through polysynaptic outputs of the STN proper leading to stimulation of midbrain dopamine neurons, or through direct activation of dopamine fibers arising from current spread beyond the STN borders (Benazzouz et al, 2000a;Bruet et al, 2001;Tan et al, 2011Tan et al, , 2012Carcenac et al, 2015).…”

The Effect of Unilateral Subthalamic Nucleus Deep Brain Stimulation on Contralateral Subthalamic Nucleus Local Field Potentials

“…The functional anatomy of the basal ganglia incorporates the brainstem and thalamic nuclei, the hypothalamus, limbic system, and cerebral cortex . The mechanism by which the contralateral beta LFP is modulated is unknown, although STN‐STN connections and other indirect crossed pathways may be relevant . The observation that unilateral subthalamotomy leads to bilateral clinical improvement also suggests that the basal ganglia on the two sides is functionally coupled and supports the hypothesis that changes in the contralateral STN are probably due to cross‐hemispheric pathways rather than volume‐conducted spread of stimulation .…”

The Effects of Deep Brain Stimulation of the Subthalamic Nucleus on Vascular Endothelial Growth Factor, Brain-Derived Neurotrophic Factor, and Glial Cell Line-Derived Neurotrophic Factor in a Rat Model of Parkinson’s Disease

“…The fact that unilateral stimulation of the left STN produced bilateral, relatively similar, effects on mRNA and protein levels may be surprising. However, a relatively recent study on the projections of the STN in the rat by Cavdar et al [54], where tracers (Fluoro Gold and biotinylated dextran) were injected into the STN unilaterally to visualize STN connects after 1 week, has demonstrated strong direct interhemispheric connections between left and right STN. Furthermore, bilateral connections of the STN were also found to the SN, as well as to several further thalamic and brainstem targets [54].…”