Thalamo-Habenular Connection Differences Between Patients With Major Depressive Disorder and Normal Controls

Background: The thalamus and habenula are thought to be key brain regions in the etiology of major depressive disorder (MDD); however, few studies have investigated the structural connection between them. We compared the number of white matter tracts between the thalamus and habenula between patient with MDD and normal controls (NCs).Methods: The habenula and thalamus region of interest masks were extracted from brain magnetic resonance imaging data and individual tractography analysis was performed. First, we compared the number of fiber connections from the habenula to the thalamus between the MDD (n = 34) and NC (n = 37) groups and also compared hemispherical differences to investigate possible asymmetries.Results: There was a significant difference in the number of tracts in the right habenula-left mediodorsal thalamus pair between the two groups. For hemispherical fiber connections, the waytotal ratio of the right ipsilateral tract between the thalamus and habenula was significantly higher than that of the left ipsilateral tract in both groups.Conclusion: The number of right habenula-left mediodorsal thalamus tracts was higher in patients with MDD than in NCs. These results indicate that MDD is related to the disintegration of the left thalamus-right habenula tract function with an increased number of tracts as a compensational mechanism.

Chemogenetic dissection of the primate prefronto-subcortical pathways for working memory and decision-making

The primate prefrontal cortex (PFC) is situated at the core of higher brain functions via neural circuits such as those linking the caudate nucleus and mediodorsal thalamus. However, the distinctive roles of these prefronto-subcortical pathways remain elusive. Combining in vivo neuronal projection mapping with chemogenetic synaptic silencing, we reversibly dissected key pathways from dorsolateral part of the PFC (dlPFC) to the dorsal caudate (dCD) and lateral mediodorsal thalamus (MDl) individually in single monkeys. We found that silencing the bilateral dlPFC-MDl projections, but not the dlPFC-dCD projections, impaired performance in a spatial working memory task. Conversely, silencing the unilateral dlPFC-dCD projection, but not the unilateral dlPFC-MDl projection, altered preference in a decision-making task. These results revealed dissociable roles of the prefronto-subcortical pathways in working memory and decision-making, representing the technical advantage of imaging-guided pathway-selective chemogenetic manipulation for dissecting neural circuits underlying cognitive functions in primates.

Mediodorsal thalamus is critical for updating during extra-dimensional shifts but not reversals in the attentional set-shifting task

Cognitive flexibility, attributed to frontal cortex, is vital for navigating the complexities of everyday life. The mediodorsal thalamus (MD), interconnected to frontal cortex, may influence cognitive flexibility. Here rats performed an attentional set-shifting task measuring intra-dimensional and extra-dimensional shifts in sensory discriminations. MD lesion rats needed more trials to learn the rewarded sensory dimension. However, once the choice response strategy was established, learning further two-choice discriminations in the same sensory dimension, and reversals of the reward contingencies in the same dimension, were unimpaired. Critically though, MD lesion rats were impaired during the extra-dimensional shift, when they must rapidly update the optimal choice response strategy. Behavioral analyses showed MD lesion rats had significantly reduced ‘on-the-fly’ correct second choice responses. Diminshed c-Fos expression in the prelimbic and orbitofrontal cortex was also documented. This evidence shows transfer of information via the MD is critical when monitoring and rapid updates in established choice response strategies are required.

Lysergic acid diethylamide differentially modulates the reticular thalamus, mediodorsal thalamus, and infralimbic prefrontal cortex: An in vivo electrophysiology study in male mice

Background: The reticular thalamus gates thalamocortical information flow via finely tuned inhibition of thalamocortical cells in the mediodorsal thalamus. Brain imaging studies in humans show that the psychedelic lysergic acid diethylamide (LSD) modulates activity and connectivity within the cortico-striato-thalamo-cortical (CSTC) circuit, altering consciousness. However, the electrophysiological effects of LSD on the neurons in these brain areas remain elusive. Methods: We employed in vivo extracellular single-unit recordings in anesthetized adult male mice to investigate the dose–response effects of cumulative LSD doses (5–160 µg/kg, intraperitoneal) upon reticular thalamus GABAergic neurons, thalamocortical relay neurons of the mediodorsal thalamus, and pyramidal neurons of the infralimbic prefrontal cortex. Results: LSD decreased spontaneous firing and burst-firing activity in 50% of the recorded reticular thalamus neurons in a dose–response fashion starting at 10 µg/kg. Another population of neurons (50%) increased firing and burst-firing activity starting at 40 µg/kg. This modulation was accompanied by an increase in firing and burst-firing activity of thalamocortical neurons in the mediodorsal thalamus. On the contrary, LSD excited infralimbic prefrontal cortex pyramidal neurons only at the highest dose tested (160 µg/kg). The dopamine D2 receptor (D2) antagonist haloperidol administered after LSD increased burst-firing activity in the reticular thalamus neurons inhibited by LSD, decreased firing and burst-firing activity in the mediodorsal thalamus, and showed a trend towards further increasing the firing activity of neurons of the infralimbic prefrontal cortex. Conclusion: LSD modulates firing and burst-firing activity of reticular thalamus neurons and disinhibits mediodorsal thalamus relay neurons at least partially in a D2-mediated fashion. These effects of LSD on thalamocortical gating could explain its consciousness-altering effects in humans.

Coordinated hippocampal-thalamic-cortical communication crucial for engram dynamics underneath systems consolidation

Systems consolidation refers to the reorganization of memory over time across brain regions. Despite recent advancements in unravelling engrams and circuits essential for this process, the exact mechanisms behind engram cell dynamics and the role of associated pathways remain poorly understood. Here, we propose a computational model to address this knowledge gap that consists of a multi-region spiking recurrent neural network subject to biologically-plausible synaptic plasticity mechanisms. By coordinating the timescales of synaptic plasticity throughout the network and incorporating a hippocampus-thalamus-cortex circuit, our model is able to couple engram reactivations across these brain regions and thereby reproduce key dynamics of cortical and hippocampal engram cells along with their interdependencies. Decoupling hippocampal-thalamic-cortical activity disrupts engram dynamics and systems consolidation. Our modeling work also yields several testable predictions: engram cells in mediodorsal thalamus are activated in response to partial cues in recent and remote recall and are crucial for systems consolidation; hippocampal and thalamic engram cells are essential for coupling engram reactivations between subcortical and cortical regions; inhibitory engram cells have region-specific dynamics with coupled reactivations; inhibitory input to mediodorsal thalamus is critical for systems consolidation; and thalamocortical synaptic coupling is predictive of cortical engram dynamics and the retrograde amnesia pattern induced by hippocampal damage. Overall, our results suggest that systems consolidation emerges from concerted interactions among engram cells in distributed brain regions enabled by coordinated synaptic plasticity timescales in multisynaptic subcortical-cortical circuits.

Longitudinal tracing of neurochemical metabolic disorders in working memory neural circuit and optogenetics modulation in rats with vascular cognitive impairment

Objective: Chronic cerebral ischemia leads to vascular cognitive impairment (VCI) that exacerbates along with ischemia time and eventually develops into dementia. Recent advances in molecular neuroimaging contribute to understand its pathological characteristics. We previously traced the anisotropic diffusion of water molecules suggests that chronic cerebral ischemia leads to irreversible progressive damage to white matter integrity. However, the abnormalities of gray matter activity following chronic cerebral ischemia remains not entirely understood.Methods: In this study, in vivo hydrogen proton magnetic resonance spectroscopy (1H-MRS) was applied to longitudinally track the neurochemical metabolic disorder of gray matter associated with working memory, and optogenetics modulation of neurochemical metabolism was performed for targeted treatment of VCI. Results: The results showed that the concentration of N-acetylaspartate (NAA) in the right hippocampus, left hippocampus, right medial prefrontal cortex (mPFC) and mediodorsal thalamus was decreased as early as 7 days after chronic cerebral ischemia, subsequently gamma-aminobutyric acid (GABA) declined whereas myo-inositol (mI) and glutamate (Glu) increased at 14 days, as well as choline (Cho) lost at 28 days, concurrently the change of Glu and GABA in the mPFC and hippocampus was ischemia time-dependent manner within 1 month. Behaviorally, working memory and object recognition memory were impaired at 14 days, 28 days that significantly correlated with neurochemical metabolic disorders. Interestingly, using optogenetics modulation of PV neurons in the mPFC, the metabolic abnormalities of NAA and GABA in working memory neural circuit could be repaired after chronic cerebral ischemia, together with behavior improvements. Conclusions: These findings suggested that as early as 1~4 weeks after chronic cerebral ischemia, the metabolism of NAA, Glu, mI and Cho was synchronously impaired in neural circuit of hippocampus-mediodorsal thalamus-mPFC, and the loss of GABA delayed in the hippocampus, and optogenetics modulation of parvalbumin (PV) neurons in the mPFC can improve the neurochemical metabolism of working memory neural circuit and enhance working memory.

Variation of connectivity across exemplar sensory and associative thalamocortical loops in the mouse

The thalamus engages in sensation, action, and cognition, but the structure underlying these functions is poorly understood. Thalamic innervation of associative cortex targets several interneuron types, modulating dynamics and influencing plasticity. Is this structure-function relationship distinct from that of sensory thalamocortical systems? Here, we systematically compared function and structure across a sensory and an associative thalamocortical loop in the mouse. Enhancing excitability of mediodorsal thalamus, an associative structure, resulted in prefrontal activity dominated by inhibition. Equivalent enhancement of medial geniculate excitability robustly drove auditory cortical excitation. Structurally, geniculate axons innervated excitatory cortical targets in a preferential manner and with larger synaptic terminals, providing a putative explanation for functional divergence. The two thalamic circuits also had distinct input patterns, with mediodorsal thalamus receiving innervation from a diverse set of cortical areas. Altogether, our findings contribute to the emerging view of functional diversity across thalamic microcircuits and its structural basis.