Spatiotemporal Dynamics of Neuroinflammation Relate to Behavioral Recovery in Rats with Spinal Cord Injury.

PURPOSE: The degree and dynamic progression of neuroinflammation after traumatic spinal cord injuries (SCI) are crucial determinants of the severity of injury and potential for recovery. We used Positron Emission Tomography (PET) to monitor neuroinflammation longitudinally, correlating it with Chemical Exchange Saturation Transfer (CEST) Magnetic Resonance Imaging (MRI) and behavior in contusion-injured rats. These studies help validate CEST metrics and confirm how imaging may be used to evaluate the efficacy of therapies and understand their mechanisms of action. PROCEDURES: 12 SCI and 4 sham surgery rats were subjected to CEST MRI and PET-Translocator Protein (TSPO) scans for 8 weeks following injury. Z-spectra from the SCI were analyzed using a 5-Lorentzian pool model for fitting. Weekly motor and somatosensory behavior were correlated with imaging metrics, which were validated through post-mortem histological and immuo-staining using ionized calcium-binding adaptor protein-1 (iba-1, microglia) and glial fibrillary acidic protein (GFAP, astrocytes). RESULTS: PET-TSPO showed widespread inflammation and post-mortem histology confirmed the presence of activated microglia. Changes in CEST and nuclear Overhauser Effect (NOE) peaks at 3.5 ppm and -1.6 ppm respectively were largest within the first week after injury and more pronounced in rostral versus caudal segments. These temporal indices of neuroinflammation corresponded to the recovery of locomotor behaviors and somatic sensation in rats with moderate contusion injury. The results confirm that CEST MRI metrics are sensitive indices of states of neuroinflammation within injured spinal cords. CONCLUSIONS: The detection of dynamic spatiotemporal features of neuroinflammation progression underscores the importance of considering their timings and locations for neuroprotective and anti-inflammatory therapies. The availability of noninvasive MRI indices of neuroinflammation may facilitate clinical trials aimed at treatments that promote recovery after SCI.

Design and construction of an interchangeable RF coil system for rodent spinal cord MR imaging at 9.4 T.

Rodent models of spinal cord injury (SCI) have been widely used in pre-clinical studies. Injuries may occur at different levels of the lumbar and thoracic cord, and the number of segments injured and their depths may vary along the spine. It is thereby challenging to build one universal RF coil that exhibits optimal performance for all spinal cord imaging applications, especially in an animal scanner with small in-bore space and limited hardware configurations. We developed an interchangeable RF coil system for a 9.4 T small animal MRI scanner, in which the users can select an optimal coil specialized for imaging specific parts of a rat spine. We also developed the associated animal management device for immobilization and positioning. The whole system allows ease of RF coil exchange, animal fixation, and positioning, and thus reduces the animal preparation time before the MRI scan significantly. Compared to a commercial general-purpose 2-cm-diameter coil that was used in our previous studies, the specialized coil optimized for Sprague-Dawley rat lumbar spinal cord imaging exhibits up to 2.4 times SNR improvement.

Compulsive alcohol consumption is regulated by dorsal striatum fast-spiking interneurons.

Compulsive alcohol consumption is a core, treatment-resistant feature of alcohol use disorder. The dorsomedial and dorsolateral striatum support goal-directed and habitual action strategies, respectively. How ethanol targets dorsolateral striatum to drive compulsive consumption is poorly understood. Parvalbumin-expressing striatal fast-spiking interneurons comprise ~1% of the total neuronal striatal population, are enriched dorsolaterally and are functionally modulated by ethanol. To test whether fast-spiking interneurons are necessary for the development of compulsive ethanol consumption, we selectively ablated these neurons in adult male and female C57BL/6 J mice undergoing a voluntary chronic intermittent ethanol consumption paradigm followed by a compulsive ethanol drinking assay. Fast-spiking interneuron ablation curtailed the development of organized ethanol lick sequence behavior, reduced ethanol consumption, and abrogated compulsive consumption of ethanol with the added bitterant quinine. In contrast, fast-spiking interneuron ablation did not affect any index of water or sucrose consumption. These data causally implicate the minority striatal fast-spiking interneuron population as a key component of compulsive ethanol consumption.

The Mouse Claustrum Is Required for Optimal Behavioral Performance Under High Cognitive Demand.

BACKGROUND: To achieve goals, organisms are often faced with complex tasks that require enhanced control of cognitive faculties for optimal performance. However, the neural circuit mechanisms underlying this ability are unclear. The claustrum is proposed to mediate a variety of functions ranging from sensory binding to cognitive control of action, but direct functional assessments of this telencephalic nucleus are lacking. METHODS: Here, we employed the Gnb4 (guanine nucleotide-binding subunit beta-4) cre driver line in mice to selectively monitor and manipulate claustrum projection neurons during 1-choice versus 5-choice serial reaction time task performance. RESULTS: Using fiber photometry, we found elevated claustrum activity prior to an expected cue during correct performance on the cognitively demanding 5-choice response assay relative to the less demanding 1-choice version of the task. Claustrum activity during reward acquisition was also enhanced when task demand was higher. Furthermore, optogenetically inhibiting the claustrum prior to the onset of the cue reduced choice accuracy on the 5-choice task but not on the 1-choice task. CONCLUSIONS: These results suggest that the claustrum supports a cognitive control function necessary for optimal behavioral performance under cognitively demanding conditions.

Activation of the Rostral Intralaminar Thalamus Drives Reinforcement through Striatal Dopamine Release.

Glutamatergic projections of the thalamic rostral intralaminar nuclei of the thalamus (rILN) innervate the dorsal striatum (DS) and are implicated in dopamine (DA)-dependent incubation of drug seeking. However, the mechanism by which rILN signaling modulates reward seeking and striatal DA release is unknown. We find that activation of rILN inputs to the DS drives cholinergic interneuron burst-firing behavior and DA D2 receptor-dependent post-burst pauses in cholinergic interneuron firing. In vivo, optogenetic activation of this pathway drives reinforcement in a DA D1 receptor-dependent manner, and chemogenetic suppression of the rILN reduces dopaminergic nigrostriatal terminal activity as measured by fiber photometry. Altogether, these data provide evidence that the rILN activates striatal cholinergic interneurons to enhance the pursuit of reward through local striatal DA release and introduce an additional level of complexity in our understanding of striatal DA signaling.

TrkB-dependent disinhibition of the nucleus accumbens is enhanced by ethanol.

The nucleus accumbens is a critical integration center for reward-related circuitry and is comprised primarily of medium spiny projection neurons. The dynamic balance of excitation and inhibition onto medium spiny neurons determines the output of this structure. While nucleus accumbens excitatory synaptic plasticity is well-characterized, inhibitory synaptic plasticity mechanisms and their potential relevance to shaping motivated behaviors is poorly understood. Here we report the discovery of long-term depression of inhibitory synaptic transmission in the mouse nucleus accumbens core. This long-term depression is postsynaptically expressed, tropomyosin kinase B (TrkB) receptor-mediated, and augmented in the presence of ethanol. Our findings support the emerging view that TrkB signaling regulates inhibitory synaptic plasticity and suggest this mechanism in the nucleus accumbens as a target for ethanol modulation of reward.

Structural Connectivity of the Anterior Cingulate Cortex, Claustrum, and the Anterior Insula of the Mouse.

The claustrum is a narrow subcortical brain structure that resides between the striatum and insular cortex. The function of the claustrum is not fully described, and while our previous work supports a role for the claustrum in top-down cognitive control of action, other evidence suggests the claustrum may be involved in detecting salient changes in the external environment. The anterior cingulate cortex (ACC) and the anterior insular (aINS) are the two major participants in the salience network of human brain regions that activate in response to salient stimuli. While bidirectional connections between the ACC and the claustrum exist from mouse to non-human primate, the aINS connectivity with claustrum remains unclear, particularly in mouse. Here, we explored structural connections of the aINS with the claustrum and ACC through adeno-associated virus neuronal tract tracer injections into the ACC and aINS of the mouse. We detected sparse projections from the claustrum to the aINS and diffuse projections from the aINS to the borders of the claustrum were observed in some cases. In contrast, the insular cortex and endopiriform nucleus surrounding the claustrum had rich interconnectivity with aINS. Additionally, we observed a modest interconnectivity between ACC and the aINS. These data support the idea that claustrum neuron responses to salient stimuli may be driven by the ACC rather than the aINS.

Anterior Cingulate Cortex Input to the Claustrum Is Required for Top-Down Action Control.

Cognitive abilities, such as volitional attention, operate under top-down, executive frontal cortical control of hierarchically lower structures. The circuit mechanisms underlying this process are unresolved. The claustrum possesses interconnectivity with many cortical areas and, thus, is hypothesized to orchestrate the cortical mantle for top-down control. Whether the claustrum receives top-down input and how this input may be processed by the claustrum have yet to be formally tested, however. We reveal that a rich anterior cingulate cortex (ACC) input to the claustrum encodes a preparatory top-down information signal on a five-choice response assay that is necessary for optimal task performance. We further show that ACC input monosynaptically targets claustrum inhibitory interneurons and spiny glutamatergic projection neurons, the latter of which amplify ACC input in a manner that is powerfully constrained by claustrum inhibitory microcircuitry. These results demonstrate ACC input to the claustrum is critical for top-down control guiding action.