In post-mitotic neurons, several tumor suppressor genes (TSGs) including p53, Rb and PTEN modulate the axon regeneration success after injury. Particularly, PTEN inhibition is a key driver of successful CNS axon regeneration after optic nerve or spinal cord injury. In contrast, in peripheral neurons, TSG influence in neuronal morphology, physiology and pathology has not been investigated to the same depth. In this study we conditionally deleted PTEN from mouse facial motoneurons ( Ptenflox/flox; Chat-Cre ) and analyzed neuronal responses in vivo with or without peripheral facial nerve injury in male and female mice. In uninjured motoneurons, PTEN loss induced somatic, axonal and nerve hypertrophy, synaptic terminal enlargement and reduction in physiological whisker movement. Despite these morphological and physiological changes, PTEN deletion positively regulated facial nerve regeneration and recovery of whisker movement after nerve injury. Regenerating PTEN deficient motoneurons upregulated P-CREB and a s...

Neurophysiological work in primates and rodents have shown the amygdala plays a central role in reward processing through connectivity with the orbitofrontal cortex (OFC) and hippocampus. However, understanding the role of oscillations in each region and their connectivity in different stages of reward processing in humans has been hampered by limitations with non-invasive methods such as poor spatial and temporal resolution. To overcome these limitations, we recorded local field potentials (LFPs) directly from the amygdala, OFC and hippocampus simultaneously in human male and female epilepsy patients performing a monetary incentive delay task. This allowed us to dissociate electrophysiological activity and connectivity patterns related to the anticipation and receipt of rewards and losses in real-time. Anticipation of reward increased high frequency gamma (HFG) (60-250 Hz) activity in the hippocampus and theta band (4-8 Hz) synchronization between amygdala and OFC, suggesting roles in memory and motivatio...

Parkinson’s disease (PD) results from a loss of dopaminergic neurons. What triggers the break-down of neuronal signaling, and how this might be compensated, is not understood. The age of onset, progression and symptoms vary between patients, and our understanding of the clinical variability remains incomplete. In this study, we investigate this, by characterizing the dopaminergic landscape in healthy and denervated striatum, using biophysical modelling. Based on currently proposed mechanisms, we model three distinct denervation patterns, and show how this affect the dopaminergic network. Depending on the denervation pattern, we show how local and global differences arise in the activity of striatal neurons. Finally, we use the mathematical formalism to suggest a cellular strategy for maintaining normal dopamine signaling following neuronal denervation. This strategy is characterized by dual enhancement of both the release and uptake capacity of dopamine in the remaining neurons. Overall, our results derive...

Gonadotropin-releasing hormone (GnRH)-secreting neurons control fertility. The release of GnRH peptide regulates the synthesis and release of both LH and FSH from the anterior pituitary. While it is known that dopamine regulates GnRH neurons, the specific dopamine receptor subtype(s) involved remain unclear. Previous studies in adult rodents have reported juxtaposition of fibers containing tyrosine hydroxylase (TH), a marker of catecholaminergic cells, onto GnRH neurons and that exogenous dopamine inhibits GnRH neurons postsynaptically through dopamine D1-like and/or D2-like receptors. Our microarray data from GnRH neurons revealed a high level of Drd4 transcripts [i.e., dopamine D4 receptor (D4R)]. Single-cell RT-PCR and immunocytochemistry confirmed GnRH cells express the Drd4 transcript and protein, respectively. Calcium imaging identified changes in GnRH neuronal activity during application of subtype-specific dopamine receptor agonists and antagonists when GABAergic and glutamatergic transmission was ...

The synaptic balance between excitation and inhibition (E/I balance) is a fundamental principle of cortical circuits, and disruptions in E/I balance are commonly linked to cognitive deficits such as impaired decision-making. Explanatory gaps remain in a mechanistic understanding of how E/I balance contributes to cognitive computations, and how E/I disruptions at the synaptic level can propagate to induce behavioral deficits. Here, we studied how E/I perturbations may impair perceptual decision-making in a biophysically-based association cortical circuit model. We found that both elevating and lowering E/I ratio, via NMDA receptor (NMDAR) hypofunction at inhibitory interneurons and excitatory pyramidal neurons, respectively, can similarly impair psychometric performance, following an inverted-U dependence. Nonetheless, these E/I perturbations differentially alter the process of evidence accumulation across time. Under elevated E/I ratio, decision-making is impulsive, overweighting early evidence and underwe...

Strong inhibitory synaptic gating of dentate gyrus granule cells (GCs), attributed largely to fast-spiking parvalbumin interneurons (PV-INs), is essential to maintain sparse network activity needed for dentate dependent behaviors. However, the contribution of PV-INs to basal and input-driven sustained synaptic inhibition in GCs and semilunar granule cells (SGCs), a sparse morphologically distinct dentate projection neuron subtype, is currently unknown. In studies conducted in hippocampal slices from mice, we find that although basal IPSCs are more frequent in SGCs and optical activation of PV-INs reliably elicited IPSCs in both GCs and SGCs, optical suppression of PV-INs failed to reduce IPSC frequency in either cell type. Amplitude and kinetics of IPSCs evoked by perforant path (PP) activation were not different between GCs and SGCs. However, the robust increase in sustained polysynaptic IPSCs elicited by paired afferent stimulation was lower in SGCs than in simultaneously recorded GCs. Optical suppressio...

In the article “Dorsal Root Ganglia Macrophages Maintain Osteoarthritis Pain,” by Ramin Raoof, Christian Martin Gil, Floris P.J.G. Lafeber, Huub de Visser, Judith Prado, Sabine Versteeg, Mirte N. Pascha, Anne L.P. Heinemans, Youri Adolfs, Jeroen Pasterkamp, John N. Wood, Simon C. Mastbergen, and

Eunyoung Bang, Annette S. Fincher, Sophie Nader, David A. Murchison, and William H. Griffith (see pages [1020–1034][1]) The aging process involves breakdown of cellular repair processes, disruption of mitochondrial function, accumulation of oxidative damage and protein degradation products,

Activity of dorsal raphe neurons is controlled by noradrenaline afferents. In this brain region, noradrenaline activates Gαq-coupled α1-adrenergic receptors (α1-AR), causing action potential (AP) firing and serotonin release. In vitro , electrical stimulation elicits vesicular noradrenaline release and subsequent activation of α1-AR to produce an EPSC (α1-AR-EPSC). The duration of the α1-AR-EPSC (∼27 s) is much longer than that of most other synaptic currents, but the factors that govern the spatiotemporal dynamics of α1-AR are poorly understood. Using an acute brain slice preparation from adult male and female mice and electrophysiological recordings from dorsal raphe neurons, we found that the time course of the α1-AR-EPSC was slow, but highly consistent within individual serotonin neurons. The amount of noradrenaline released influenced the amplitude of the α1-AR-EPSC without altering the time constant of decay suggesting that once released, extracellular noradrenaline was cleared efficiently. Reuptake ...

Stable neural function requires an energy supply that can meet the intense episodic power demands of neuronal activity. Neurons have presumably optimized the volume of their bioenergetic machinery to ensure these power demands are met, but the relationship between presynaptic power demands and the volume available to the bioenergetic machinery has never been quantified. Here, we estimated the power demands of six motor nerve terminals in female Drosophila larvae through direct measurements of neurotransmitter release and Ca2+ entry, and via theoretical estimates of Na+ entry and power demands at rest. Electron microscopy revealed that terminals with the highest power demands contained the greatest volume of mitochondria, indicating that mitochondria are allocated according to presynaptic power demands. In addition, terminals with the greatest power demand-to-volume ratio (∼66 nmol·min−1·µl−1) harbor the largest mitochondria packed at the greatest density. If we assume sequential and complete oxidation of g...