Context-dependent relationships between locus coeruleus firing patterns and coordinated neural activity in the anterior cingulate cortex

Ascending neuromodulatory projections from the locus coeruleus (LC) affect cortical neural networks via the release of norepinephrine (NE). However, the exact nature of these neuromodulatory effects on neural activity patterns in vivo is not well understood. Here we show that in awake monkeys, LC activation is associated with changes in coordinated activity patterns in the anterior cingulate cortex (ACC). These relationships, which are largely independent of changes in firing rates of individual ACC neurons, depend on the type of LC activation: ACC pairwise correlations tend to be reduced when ongoing (baseline) LC activity increases but enhanced when external events evoke transient LC responses. Both relationships covary with pupil changes that reflect LC activation and arousal. These results suggest that modulations of information processing that reflect changes in coordinated activity patterns in cortical networks can result partly from ongoing, context-dependent, arousal-related changes in activation of the LC-NE system.

An autopsied case report of spastic paraplegia with thin corpus callosum carrying a novel mutation in the SPG11 gene: widespread degeneration with eosinophilic inclusions

Background The detailed neuropathological features of patients with autosomal recessive hereditary spastic paraplegia with a thin corpus callosum (TCC) and SPG11 mutations are poorly understood, as only a few autopsies have been reported. Herein, we describe the clinicopathological findings of a patient with this disease who received long-term care at our medical facility. Case presentation A Japanese man exhibited a mild developmental delay in early childhood and intellectual disability, followed by the appearance of a spastic gait by age 13. At the age of 25 years, he became bedridden and needed a ventilator. Genetic analysis revealed a homozygous splice site variant in the SPG11 gene (c. 4162–2A > G) after the provision of genetic counselling and acquisition of informed consent from his parents. He died of pneumonia at the age of 44. His brain weighed 967 g and was characterized by a TCC, and his spinal cord was flattened. Microscopically, degeneration was observed in the posterior spinocerebellar tract, the gracile fasciculus, and the posterior column in addition to the corticospinal tract. Marked neuronal loss and gliosis were observed in the anterior horn, Clarke’s column, and hypoglossal and facial nuclei. Various types of neurons, in addition to motor neurons, showed coarse eosinophilic granules that were immunoreactive for p62. The loss of pigmented neurons with gliosis was apparent in both the substantia nigra and locus coeruleus. Lateral geniculate body degeneration was a characteristic feature of this patient. Furthermore, peripheral Lewy body-related α-synucleinopathy and scattered α-synuclein–immunoreactive neurites in the locus coeruleus and reticular formation of the brainstem were observed. Conclusions In patients with hereditary spastic paraplegia with SPG11 mutations, a variety of clinical phenotypes develop due to widespread lesions containing p62-immunoreactive neuronal cytoplasmic inclusions. We herein report the lateral geniculate body as another degenerative site related to SPG11-related pathologies that should be studied in future investigations.

Hypocretin in locus coeruleus and dorsal raphe nucleus mediates inescapable footshock stimulation (IFS)-induced REM sleep alteration

Hypocretin (hcrt) is a stress-reacting neuropeptide mediating arousal and energy homeostasis. An inescapable footshock stimulation (IFS) could initiate the hcrt release from the lateral hypothalamus (LHA) and suppresses rapid eye movement (REM) sleep in rodents. However, the effects of the IFS-induced hcrts on REM-off nuclei, the locus coeruleus (LC) and dorsal raphe nucleus (DRN), remained unclear. We hypothesized that the hcrt projections from the LHA to LC or DRN mediate IFS-induced sleep disruption. Our results demonstrated that the IFS increased hcrt expression and the neuronal activities in the LHA, hypothalamus, brainstem, thalamus, and amygdala. Suppressions of REM sleep and slow wave activity during non-REM (NREM) sleep caused by the high expression of hcrts were blocked when a non-specific and dual hcrt receptor antagonist was administered into the LC or DRN. Furthermore, the IFS also caused an elevated innate anxiety, but was limitedly influenced by the hcrt antagonist. This result suggests that the increased hcrt concentrations in the LC and DRN mediate stress-induced sleep disruptions and might partially involve IFS-induced anxiety.

Association of Cognitive Impairment With Free Water in the Nucleus Basalis of Meynert and Locus Coeruleus to Transentorhinal Cortex Tract

Objective:Determine the relationship between diffusion microstructure and early changes in Alzheimer’s disease (AD) severity as assessed by clinical diagnosis, cognitive performance, dementia severity, and plasma concentrations of neurofilament light chain.Methods:Diffusion MRI scans were collected on cognitively normal participants (CN), patients with early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and AD. Free water (FW) and FW-corrected fractional anisotropy were calculated in the locus coeruleus to transentorhinal cortex tract, four magnocellular regions of the basal forebrain (e.g. nucleus basalis of Meynert), entorhinal cortex, and hippocampus. All patients underwent a battery of cognitive assessments; neurofilament light chain levels were measured in plasma samples.Results:FW was significantly higher in EMCI compared to CN in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus (mean Cohen d = 0.54; pfdr<0.05). FW was significantly higher in AD compared to CN in all the examined regions (mean Cohen d = 1.41; pfdr<0.01). Additionally, FW in the hippocampus, entorhinal cortex, nucleus basalis of Meynert, and locus coeruleus to transentorhinal cortex tract positively correlated with all five cognitive impairment metrics, and neurofilament light chain levels (mean r2 = 0.10; pfdr<0.05).Conclusions:These results show that higher FW is associated with greater clinical diagnosis severity, cognitive impairment, and neurofilament light chain. They also suggest that FW elevation occurs in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus in the transition from CN to EMCI, while other basal forebrain regions and the entorhinal cortex are not affected until a later stage of AD. FW is a clinically relevant and non-invasive early marker of structural changes related to cognitive impairment.

Locus Coeruleus Optogenetic Modulation: Lessons Learned from Temporal Patterns

After reviewing seminal studies using optogenetics to interrogate the functional role of the locus coeruleus in behavior, we conclude that differences in firing rates and firing patterns of locus coeruleus neurons contribute to locus coeruleus nucleus heterogeneity by recruiting different output circuitry, and differentially modifying behavior. The outcomes initiated by different optogenetic input activation patterns and frequencies can have opposite consequences for behavior, activate different neurons in the same target structure, be supported by distinct adrenoceptors and vary with behavioral state.

The Locus Coeruleus Noradrenaline System in Delirium

Delirium is a brain state involving severe brain dysfunction affecting cognitive and attentional capacities. Our opinion statement review aims to elucidate the relationship between abnormal arousal and locus coeruleus (LC) activity in cognitive dysfunction and inattention in delirium states. We propose (1) that enhanced noradrenaline release caused by altered arousal in hyperactive delirium states leads to increased noradrenergic transmission within the LC and subcortical and cortical brain regions including the prefrontal cortex and hippocampus, thus affecting how attention and cognition function. In hypoactive delirium states, however, we are presuming (2) that less arousal will cause the release of noradrenaline to diminish in the LC, followed by reduced noradrenergic transmission in cortical and subcortical brain areas concentrated within the prefrontal cortex and hippocampus, leading to deficient attention and cognitive processing. Studies addressing the measurement of noradrenaline and its derivatives in biomaterial probes regarding delirium are also covered in this article. In conclusion, the LC-NA system plays a crucial role in generating delirium. Yet there have been no large-scale studies investigating biomarkers of noradrenaline to help us draw conclusions for improving delirium’s diagnosis, treatment, and prognosis, and to better understand its pathogenesis.

Locus coeruleus neurons encode the subjective difficulty of triggering and executing actions

The brain stem noradrenergic nucleus locus coeruleus (LC) is involved in various costly processes: arousal, stress, and attention. Recent work has pointed toward an implication in physical effort, and indirect evidence suggests that the LC could be also involved in cognitive effort. To assess the dynamic relation between LC activity, effort production, and difficulty, we recorded the activity of 193 LC single units in 5 monkeys performing 2 discounting tasks (a delay discounting task and a force discounting task), as well as a simpler target detection task where conditions were matched for difficulty and only differed in terms of sensory-motor processes. First, LC neurons displayed a transient activation both when monkeys initiated an action and when exerting force. Second, the magnitude of the activation scaled with the associated difficulty, and, potentially, the corresponding amount of effort produced, both for decision and force production. Indeed, at action initiation in both discounting tasks, LC activation increased in conditions associated with lower average engagement rate, i.e., those requiring more cognitive control to trigger the response. Decision-related activation also scaled with response time (RT), over and above task parameters, in line with the idea that it reflects the amount of resources (here time) spent on the decision process. During force production, LC activation only scaled with the amount of force produced in the force discounting task, but not in the control target detection task, where subjective difficulty was equivalent across conditions. Our data show that LC neurons dynamically track the amount of effort produced to face both cognitive and physical challenges with a subsecond precision. This works provides key insight into effort processing and the contribution of the noradrenergic system, which is affected in several pathologies where effort is impaired, including Parkinson disease and depression.