Mild traumatic brain injury (mTBI) can initiate complex pathophysiological changes in the brain. Numerous cellular and molecular mechanisms underlying these pathologic changes are altered after injury, including those involved in energy utilization, excitotoxicity, ionic disturbances, and inflammation. It is thought that targeting multiple mechanisms may be necessary to produce meaningful reductions in brain pathology and to improve outcome. Previous studies have reported that the anti-diabetic drug metformin can also affect inflammatory, cell survival, and metabolic outcomes, possibly by acting on multiple targets and/or pathways. We therefore questioned whether metformin treatment can reduce pathology after repeat mild closed head injury (rmCHI) in male C57Bl/6 mice. We found that metformin, administered acutely after each head impact, resulted in markedly reduced white matter damage, astrogliosis, loss of hippocampal parvalbumin neurons, and improved mitochondrial function. In addition, both motor and c...

The co-chaperone FKBP51, encoded by the Fkbp5 gene, has been identified as central risk factor for anxiety-related disorders and stress system dysregulation. In the brain, the oval bed nucleus of the stria terminalis (ovBNST) has been implicated in stress-induced anxiety. However, the role of Fkbp5 in the ovBNST and its impact on anxiety-like behavior have remained unknown. Here we show in mice that Fkbp5 in the ovBNST is reactive to acute stress and co-expressed with the stress-regulated neuropeptides Tac2 and Crh . Subsequently, results obtained from viral-mediated manipulation indicate that Fkbp5 overexpression (OE) in the ovBNST results in an anxiolytic-like tendency regarding behavior and endocrinology, whereas a Fkbp5 knockout exposed a clear anxiogenic phenotype, indicating that native ovBNST expression and regulation is necessary for normal anxiety-related behavior. Notably, our data suggests that a stress-induced increase of Fkbp5 in the ovBNST may in fact have a protective role, leading to a tran...

To competently navigate the world, individuals must flexibly balance distinct aspects of social gaze, orienting toward others and inhibiting orienting responses, depending on the context. These behaviors are often disrupted in patient populations treated with serotonergic drugs. However, the field lacks a clear understanding of how the serotonergic system mediates social orienting and inhibiting behaviors. Here, we tested how increasing central concentrations of serotonin with the direct precursor 5-Hydroxytryptophan (5-HTP) would modulate the ability of rhesus macaques (both sexes) to use eye movements to flexibly orient to, or inhibit orienting to, faces. Systemic administrations of 5-HTP effectively increased central serotonin levels and impaired flexible orientation and inhibition. Critically, 5-HTP selectively impaired the ability of monkeys to inhibit orienting to face images, whereas it similarly impaired orienting to face and control images. 5-HTP also caused monkeys to perseverate on their gaze re...

Sequence learning is a ubiquitous facet of human and animal cognition. Here, using a common sequence reproduction task, we investigated whether and how the ordinal and relational structures linking consecutive elements are acquired by human adults, children, and macaque monkeys. While children and monkeys exhibited significantly lower precision than adults for spatial location and temporal order information, only monkeys appeared to exceedingly focus on the first item. Most importantly, only humans, regardless of age, spontaneously extracted the spatial relations between consecutive items and used a chunking strategy to compress sequences in working memory. Monkeys did not detect such relational structures, even after extensive training. Monkey behavior was captured by a conjunctive coding model, whereas a chunk-based conjunctive model explained more variance in humans. These age- and species-related differences are indicative of developmental and evolutionary mechanisms of sequence encoding and may provid...

When we look at our body parts, we are immediately aware that they belong to us and we rarely doubt about the integrity, continuity and sense of ownership of our body. Despite this certainty, immersive virtual reality (IVR) may lead to a strong feeling of embodiment over an artificial body part seen from a first-person perspective. Although such feeling of ownership (FO) has been described in different situations, it is not yet understood how this phenomenon is generated at neural level. To track the real-time brain dynamics associated with FO, we delivered transcranial magnetic stimuli over the hand region in the primary motor cortex and simultaneously recorded electroencephalography in 19 healthy volunteers (11M/8F) watching IVR renderings of anatomically plausible (full-limb) vs implausible (hand disconnected from the forearm) virtual limbs. Our data show that embodying a virtual hand is temporally associated with a rapid drop of cortical activity of the onlookers’ hand region in the primary motor corte...

Texture is an important visual attribute for surface pattern discrimination and therefore object segmentation, but the neural bases of texture perception are largely unknown. Previously, we demonstrated that the responses of V4 neurons to naturalistic texture patches are sensitive to four key features of human texture perception: coarseness, directionality, regularity, and contrast. To begin to understand how distinct texture perception emerges from the dynamics of neuronal responses, in 2 macaque monkeys (1 male, 1 female), we investigated the relative contribution of the four texture attributes to V4 responses in terms of the strength and timing of response modulation. We found that the different feature dimensions are associated with different temporal dynamics. Specifically, the response modulation associated with directionality and regularity was significantly delayed relative to that associated with coarseness and contrast, suggesting that the latter are fundamentally simpler feature dimensions. The ...

Proprioception, the sense of limb and body position, generates a map of the body that is essential for proper motor control, yet we know little about precisely how neurons in proprioceptive pathways are wired. Defining the anatomy of secondary neurons in the spinal cord that integrate and relay proprioceptive and potentially cutaneous information from the periphery to the cerebellum is fundamental to understanding how proprioceptive circuits function. Here, we define the unique anatomical trajectories of long-range direct and indirect spinocerebellar pathways as well as local intersegmental spinal circuits using genetic tools in both male and female mice. We find that Clarke’s column (CC) neurons, a major contributor to the direct spinocerebellar pathway, has mossy fiber terminals that diversify extensively in the cerebellar cortex with axons terminating bilaterally, but with no significant axon collaterals within the spinal cord, medulla, or cerebellar nuclei. By contrast, we find that two of the indirect...

Spreading depolarizations (SDs) of gray matter occur in the brain, in different pathological conditions, and cause varying degrees of tissue damage depending on the extent of metabolic burden on the tissue. As might be expected for such large depolarizations, neurons exhibit bursts of action potentials as the wave propagates. However, the specific role of action potentials in SD propagation is unclear. This is potentially consequential, since sodium channel modulation has not been considered as a therapeutic target for SD-associated disorders, due to ambiguous experimental evidence. Using whole-cell electrophysiology and single-photon imaging in acute cortical slices from male C57Bl6 mice, we tested the effects of action potential blockade on SDs generated by two widely used induction paradigms. We found that action potential blockade using tetrodotoxin (TTX) restricted propagation of focally induced SDs, and significantly reduced the amplitude of neuronal depolarization, as well as its Ca2+ load. TTX also...

The binaural interaction component (BIC) is a sound-evoked electrophysiological signature of binaural processing in the auditory brainstem that has received attention as a potential biomarker for spatial hearing deficits. Yet the number of trials necessary to evoke the BIC, or its measurability, seems to vary across species: while it is easily measured in small rodents, it has proven to be highly variable and less reliably measured in humans. This has hindered its potential use as a diagnostic tool. Further measurements of the BIC across a wide range of species could help us better understand its origin and the possible reasons for the variation in its measurability. Statistical analysis on the function relating BIC DN1 amplitude and the interaural time difference has been performed in only a few small rodent species, thus is remains to be shown how the results apply to more taxonomically diverse mammals, and those with larger heads. To fill this gap we measured BICs in Rhesus Macaque. We show the overall ...

Angelman syndrome (AS) is a neurodevelopmental disorder with unique behavioral phenotypes, seizures, and distinctive electroencephalographic (EEG) patterns. Recent studies identified motor, social communication, and learning and memory deficits in a CRISPR engineered rat model with a complete maternal deletion of the Ube3a gene. It is unknown whether this model recapitulates other aspects of the clinical disorder. We report here the effect of Ube3a maternal deletion in the rat on epileptiform activity, seizure threshold, and quantitative EEG. Using video-EEG monitoring, we assessed spectral power and epileptiform activity early postnatally through adulthood. While EEG power was similar to wildtype (WT) at 1.5 weeks postnatally, at all other ages analyzed, our findings were similar to the AS phenotype in mice and humans with significantly increased delta power. Analysis of epileptiform activity in juvenile and adult rats showed increased time spent in epileptiform activity in AS compared to WT rats. We eval...