All pathways targeting the thalamus terminate directly onto the thalamic projection cells. As these cells lack local excitatory interconnections, their computations are fundamentally defined by the type and local convergence patterns of the extrinsic inputs. These two key variables, however, remain poorly defined for the “higher order relay” (HO) nuclei that constitute most of the thalamus in large-brained mammals, including humans. Here, we systematically analyzed the input landscape of a representative HO nucleus of the mouse thalamus, the posterior nucleus (Po). We examined in adult male and female mice the neuropil distribution of terminals immunopositive for markers of excitatory or inhibitory neurotransmission, mapped input sources across the brain and spinal cord and compared the intranuclear distribution and varicosity size of axons originated from each input source. Our findings reveal a complex landscape of partly overlapping input-specific microdomains. Cortical layer 5 afferents from somatosens...

The axon initial segment (AIS) generates action potentials and maintains neuronal polarity by regulating the differential trafficking and distribution of proteins, transport vesicles, and organelles. Injury and disease can disrupt the AIS, and the subsequent loss of clustered ion channels and polarity mechanisms may alter neuronal excitability and function. However, the impact of AIS disruption on axon regeneration after injury is unknown. We generated male and female mice with AIS-deficient multipolar motor neurons by deleting AnkyrinG (AnkG), the master scaffolding protein required for AIS assembly and maintenance. We found that after nerve crush, neuromuscular junction (NMJ) reinnervation was significantly delayed in AIS-deficient motor neurons compared to control mice. In contrast, loss of AnkG from pseudo-unipolar sensory neurons did not impair axon regeneration into the intraepidermal nerve fiber layer. Even after AIS-deficient motor neurons reinnervated the NMJ, they failed to functionally recover d...

The inspiratory rhythm generator, located in the brainstem preBötzinger Complex (preBötC), is dependent on glutamatergic signaling and is affected profoundly by opioids. Here, we used organotypic slice cultures of the newborn mouse brainstem of either sex in combination with genetically encoded sensors for Ca2+, glutamate, and GABA to visualize Ca2+, glutamatergic and GABAergic signaling during spontaneous rhythm and in the presence of DAMGO. During spontaneous rhythm, the glutamate sensor SF-iGluSnFR.A184S revealed punctate synapse-like fluorescent signals along dendrites and somas in the preBötC with decay times that were prolonged by the glutamate uptake blocker (TFB-TBOA). The GABA sensor iGABASnFR showed a more diffuse fluorescent signal during spontaneous rhythm. Rhythmic Ca2+- and glutamate transients had an inverse relationship between the spontaneous burst frequency and the burst amplitude of the Ca2+ and glutamate signals. A similar inverse relationship was observed when bath applied DAMGO reduce...

To understand a dialogue, we need to know the topics that are being discussed. This enables us to integrate our knowledge of what was said previously, to interpret the current dialogue. This study involved a large-scale behavioural experiment conducted online and a separate fMRI experiment, both testing human participants. In both, we selectively manipulated knowledge about the narrative content of dialogues, presented in short videos. The clips were scenes from situation comedies that were split into two parts. The speech in the part 1 clips could either be presented normally or spectrally rotated to render it unintelligible. The part 2 clips that concluded the scenes were always presented normally. The behavioural experiment showed that knowledge of the preceding narrative boosted memory for the part 2 clips as well as increased the inter-subject semantic similarity of recalled descriptions of the dialogues. The fMRI experiment replicated the finding that prior knowledge improved memory for the conclusio...

Severe brain metabolic dysfunction and amyloid-beta accumulation are key hallmarks of Alzheimer’s disease. While astrocytes contribute to both pathological mechanisms, the role of their mitochondria, which is essential for signalling and maintenance of these processes, has been largely understudied. The current work provides the first direct evidence that the mitochondrial metabolic switch 17β-hydroxysteroid dehydrogenase type 10 (17βHSD10) is expressed and active in murine astrocytes from different brain regions. While it is known that this protein is overexpressed in the brains of Alzheimer’s disease patients, we found that 17βHSD10 is also upregulated in astrocytes exposed to amyloidogenic and ischemic stress. Importantly, such catalytic overexpression of 17βHSD10 inhibits mitochondrial respiration during increased energy demand. This observation contrasts with what has been found in neuronal and cancer model systems, which suggests astrocyte-specific mechanisms mediated by the protein. Furthermore, the...

The ability to detect faces in the environment is of utmost ecological importance for human social adaptation. While face categorization is efficient, fast and robust to sensory degradation, it is massively impaired when the facial stimulus does not match the natural contrast statistics of this visual category, i.e., the typically experienced ordered alternation of relatively darker and lighter regions of the face. To clarify this phenomenon, we characterized the contribution of natural contrast statistics to face categorization. Specifically, 31 human adults viewed various natural images of non-face categories at a rate of 12 Hz, with highly variable images of faces occurring every eight stimuli (1.5 Hz). As in previous studies, neural responses at 1.5 Hz as measured with high-density EEG provided an objective neural index of face categorization. Here, when face images were shown in their naturally experienced contrast statistics, the 1.5 Hz face categorization response emerged over occipito-temporal elec...

Motor adaptation is crucial for performing accurate movements in a changing environment and relies on the cerebellum. Although cerebellar involvement has been well characterized, the neurochemical changes in the cerebellum underpinning human motor adaptation remain unknown. We used a novel magnetic resonance spectroscopic imaging (MRSI) technique to measure changes in the inhibitory neurotransmitter GABA in the human cerebellum during visuomotor adaptation. Participants ( n = 17, six female) used their right hand to adapt to a rotated cursor in the scanner, compared with a control task requiring no adaptation. We spatially resolved adaptation-driven GABA changes at the cerebellar nuclei and cerebellar cortex in the left and the right cerebellar hemisphere independently and found that simple right-hand movements increase GABA in the right cerebellar nuclei and decreases GABA in the left. When isolating adaptation-driven GABA changes, we found that GABA in the left cerebellar nuclei and the right cerebellar ...

Action potential (AP) shape is a critical electrophysiological parameter, in particular because it strongly modulates neurotransmitter release. As it greatly varies between neuronal types, AP shape is also used to distinguish neuronal populations. For instance, AP duration ranges from hundreds of microseconds in cerebellar granule cells to 2-3 milliseconds in substantia nigra pars compacta (SNc) dopaminergic (DA) neurons. While most of this variation across cell types seems to arise from differences in the voltage- and calcium-gated ion channels expressed, a few studies suggested that dendritic morphology also affects AP shape. AP duration also displays significant variability in a same neuronal type, although the determinants of these variations are poorly known. Using electrophysiological recordings, morphological reconstructions and realistic Hodgkin-Huxley modeling, we investigated the relationships between dendritic morphology and AP shape in rat SNc DA neurons from both sexes. In this neuronal type w...

Cochlear amplification enables the enormous dynamic range of hearing through amplifying cochlear responses to low-to-moderate-level sounds and compressing them to loud sounds. Amplification is attributed to voltage-dependent electromotility of mechanosensory outer hair cells (OHCs) driven by changing voltages developed across their cell membranes. At low frequencies, these voltage changes are dominated by intracellular receptor potentials (RPs). However, OHC membranes have electrical low-pass filter properties that attenuate high-frequency RPs, which should potentially attenuate amplification of high-frequency cochlear responses and impede high-frequency hearing. We made in vivo intracellular and extracellular electrophysiological measurements from the organ of Corti of male and female mice of the CBA/J strain, with excellent high-frequency hearing, and from the CD-1 mouse strain, which has sensitive hearing below 12 kHz, but loses high-frequency hearing within a few weeks post-partum. The CD-1 mouse strai...