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 ...

Ghrelin receptor, also known as growth hormone secretagogue receptor (GHS-R1a), is coexpressed with its truncated isoform GHS-R1b, which does not bind ghrelin or signal, but oligomerizes with GHS-R1a, exerting a complex modulatory role that depends on its relative expression. D1 dopamine receptor (D1R) and D5R constitute the two D1-like receptor subtypes. Previous studies showed that GHS-R1b also facilitates oligomerization of GHS-R1a with D1R, conferring GHS-R1a distinctive pharmacological properties. Those include a switch in the preferred coupling of GHS-R1a from Gq to Gs and the ability of D1R/D5R agonists and antagonists to counteract GHS-R1a signaling. Activation of ghrelin receptors localized in the ventral tegmental area (VTA) seems to play a significant role in the contribution of ghrelin to motivated behavior. In view of the evidence indicating that dopaminergic cells of the VTA express ghrelin receptors and D5R, but not D1R, we investigated the possible existence of functional GHS-R1a:GHS-R1b:D5...

The precise location of the human female genital representation field in the primary somatosensory cortex (S1) is controversial and its capacity for use-associated structural variation as a function of sexual behavior remains unknown. We used a functional magnetic resonance imaging (fMRI)-compatible sensory-tactile stimulation paradigm to functionally map the location of the female genital representation field in 20 adult women. Neural response to tactile stimulation of the clitoral region (vs right hand) identified individually-diverse focal bilateral activations in dorsolateral areas of S1 (BA1–BA3) in alignment with anatomic location. We next used cortical surface analyses to assess structural thickness across the 10 individually most activated vertices per hemisphere for each woman. We show that frequency of sexual intercourse within 12 months is correlated with structural thickness of the individually-mapped left genital field. Our results provide a precise functional localization of the female genita...

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...

Memory retrieval is thought to depend on the reinstatement of cortical memory representations guided by pattern completion processes in the hippocampus. The lateral entorhinal cortex (LEC) is one of the intermediary regions supporting hippocampal–cortical interactions and houses neurons that prospectively signal past events in a familiar environment. To investigate the functional relevance of the activity of the LEC for cortical reinstatement, we pharmacologically inhibited the LEC and examined its impact on the stability of ensemble firing patterns in one of the efferent targets of the LEC, the medial prefrontal cortex (mPFC). When male rats underwent multiple epochs of identical stimulus sequences in the same environment, the mPFC maintained a stable ensemble firing pattern across repetitions, particularly when the sequence included pairings of neutral and aversive stimuli. With LEC inhibition, the mPFC still formed an ensemble pattern that accurately captured stimuli and their associations within each e...

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...

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,