The brain has the extraordinary capacity to construct predictive models of the environment by internalizing statistical regularities in the sensory inputs. The resulting sensory expectations shape how we perceive and react to the world; at the neural level, this relates to decreased neural responses to expected than unexpected stimuli (‘expectation suppression’). Crucially, expectations may need revision as context changes. However, existing research has often neglected this issue. Further, it is unclear whether contextual revisions apply selectively to expectations relevant to the task at hand, hence serving adaptive behaviour. The present fMRI study examined how contextual visual expectations spread throughout the cortical hierarchy as we update our beliefs. We created a volatile environment: two alternating contexts contained different sequences of object images, hence producing context-dependent expectations that needed revision when the context changed. Human participants of both sexes attended a trai...

The thalamus is an important hub for sensory information and participates in sensory perception, regulation of attention, arousal and sleep. These functions are executed primarily by glutamatergic thalamocortical neurons that extend axons to the cortex and initiate cortico-thalamocortical connectional loops. However, the thalamus also contains projection GABAergic neurons that do not engage in direct communication with the cortex. Here, we have harnessed recent insight into the development of the intergeniculate (IGL) and the ventrolateral geniculate (LGv) to specifically target and manipulate thalamic projection GABAergic neurons in female and male mice. Our results show that thalamic GABAergic neurons of the IGL and LGv receive retinal input from diverse classes of ipRGCs, but not from the M1 ipRGC type. We describe the synergistic role of the photoreceptor melanopsin and the thalamic neurons of the IGL/LGv in circadian entrainment to dim light. We identify a requirement for the thalamic IGL/LGv in the r...

To date, social and non-social decisions have been studied largely in isolation. Consequently, the extent to which social and non-social forms of decision uncertainty are integrated using shared neurocomputational resources remains elusive. Here, we address this question using simultaneous EEG-fMRI in healthy human participants (young adults of both sexes) and a task in which decision evidence in social and non-social contexts varies along comparable scales. First, we identify time-resolved build-up of activity in the EEG, akin to a process of evidence accumulation, across both contexts. We then use the endogenous trial-by-trial variability in the slopes of these accumulating signals to construct parametric fMRI predictors. We show that a region of the posterior-medial frontal cortex (pMFC) uniquely explains trial-wise variability in the process of evidence accumulation in both social and non-social contexts. We further demonstrate a task-dependent coupling between the pMFC and regions of the human valuati...

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. In this study, we generated a transgenic model by crossing germline Parkin-/- mice with PolgAD257A mice, an established model of premature aging and mitochondrial stress. We hypothesized that loss of Parkin-/- in PolgAD257A/D257A mice would exacerbate mitochondrial dysfunction, leading to loss of dopamine neurons and nigral-striatal specific neurobehavioral motor dysfunction. We found that aged Parkin-/-/PolgAD257A/D257A male and female mice exhibited severe behavioral deficits, nonspecific to the nigral-striatal pathway, with neither dopaminergic neurodegeneration nor reductions in striatal dopamine. We saw no difference in expression levels of nuclear-encoded subunits of mitochondrial markers and mitochondrial complex I and IV activities, though we did observe substantial reductions in mitochondrial-encoded COX41I, indicating mitochondrial dysfunction as a result of PolgAD257A/...

HuR is an RNA-binding protein implicated in RNA processing, stability, and translation. Previously, we examined protein synthesis in dorsal root ganglion (DRG) neurons treated with inflammatory mediators using ribosome profiling. We found that the HuR consensus binding element was enriched in transcripts with elevated translation. HuR is expressed in the soma of nociceptors and their axons. Pharmacologic inhibition of HuR with the small molecule CMLD-2 reduced the activity of mouse and human sensory neurons. Peripheral administration of CMLD-2 in the paw or genetic elimination of HuR from sensory neurons diminished behavioral responses associated with NGF and IL-6 induced allodynia in male and female mice. Genetic disruption of HuR altered the proximity of mRNA decay factors near a key neurotrophic factor (TrkA). Collectively, the data suggest that HuR is required for local control of mRNA stability and reveals a new biological function for a broadly conserved post-transcriptional regulatory factor. SIGNI...

Hb9 ( Mnx1 ) is a transcription factor described as a spinal cord motor neuron (MN)-specific marker critical factor for the postmitotic specification of these cells. To date, expression of Hb9 in other cell types has not previously been reported. We performed a fate-mapping approach to examine distributions of Hb9-expressing cells and their progeny (‘Hb9-lineage cells’) within the embryonic and adult spinal cord of Hb9cre;Ai14 mice. We found that Hb9-lineage cells are distributed in a gradient of increasing abundance throughout the rostrocaudal spinal cord axis during embryonic and postnatal stages. Furthermore, although the majority of Hb9-lineage cells at cervical spinal cord levels are MNs, at more caudal levels, Hb9-lineage cells include small-diameter dorsal horn neurons, astrocytes, and oligodendrocytes. In the peripheral nervous system, we observed a similar phenomenon with more abundant Hb9-lineage Schwann cells in muscles of the lower body versus upper body muscles. We cultured spinal cord progeni...

Circadian rhythms are biological processes that cycle across 24 hours and regulate many facets of neurophysiology, including learning and memory. Circadian variation in spatial memory task performance is well-documented; however, the effect of sex across circadian time remains unclear. Additionally, little is known regarding the impact of time-of-day on hippocampal neuronal physiology. Here, we investigated the influence of both sex and time-of-day on hippocampal neurophysiology and memory in mice. Performance on the object location memory (OLM) task depended on both circadian time and sex, with memory enhanced at night in males but during the day in females. Long-term synaptic potentiation (LTP) magnitude at CA3-CA1 synapses was greater at night compared to day in both sexes. Next, we measured spontaneous synaptic excitation and inhibition onto CA1 pyramidal neurons. Frequency and amplitude of inhibition was greater during the day compared to night, regardless of sex. Frequency and amplitude of excitation...

Categorization is an essential cognitive and perceptual process for decision making and recognition. The posterior parietal cortex (PPC), particularly the lateral intraparietal (LIP) area has been suggested to transform visual feature encoding into abstract categorical representations. By contrast, areas closer to sensory input, such as the middle temporal (MT) area, encode stimulus features but not more abstract categorical information during categorization tasks. Here, we compare the contributions of the medial superior temporal (MST) and LIP areas in category computation by recording neuronal activity in both areas from two male rhesus macaques trained to perform a visual motion categorization task. MST is a core motion processing area interconnected with MT, and often considered an intermediate processing stage between MT and LIP. Here we show that MST exhibits robust decision-correlated motion category encoding and working memory encoding similar to LIP, suggesting that MST plays a substantial role in...

Jixiang Zhang, Jazzmine M. Junigan, Ronnie Trinh, Annemieke Kavelaars, Cobi J. Heijnen, et al. (see pages [7862–7874][1]) Chemotherapy-induced peripheral neuropathy (CIPN) increases pain sensitivity and can produce spontaneous pain in the distal appendages of many cancer patients. The symptoms