Biology subjects

Fioravante, D.

Publications and source records attributed to Fioravante, D..

3 recordsLinked to original sources

bioRxiv2021

Short-term plasticity persists in the absence of PKC phosphorylation of Munc18-1

Post tetanic potentiation (PTP) is a form of short-term plasticity that lasts for tens of seconds following a burst of presynaptic activity. It has been proposed that PTP arises from protein kinase C (PKC) phosphorylation of Munc18-1, an SM (Sec1/Munc-18 like) family protein that is essential for release. To test this model, we made a knockin mouse in which all Munc18-1 PKC phosphorylation sites were eliminated through serine-to-alanine point mutations (Munc18-1 SA mice). Expression of Munc18-1 was not altered in Munc18-1SA mice, and there were no obvious behavioral phenotypes. At the hippocampal CA3 to CA1 synapse, and the granule cell parallel fiber to Purkinje cell (PF to PC) synapse, basal transmission was largely normal except for small decreases in paired-pulse facilitation that are consistent with a slight elevation in release probability. Phorbol esters that mimic activation of PKC by diacylglycerol still increased synaptic transmission in Munc18-1 SA mice. In Munc18-1 SA mice, 70% of PTP remained at CA3 to CA1 synapses, and the amplitude of PTP was not reduced at PF to PC synapses. These findings indicate that at both CA3 to CA1 and PF to PC synapses, phorbol esters and PTP enhance synaptic transmission primarily by mechanisms that are independent of PKC phosphorylation of Munc18-1. Significance StatementA leading mechanism for a prevalent form of short-term plasticity, post-tetanic potentiation (PTP), involves protein kinase C phosphorylation of Munc18-1. This study tests this mechanism by creating a knock in mouse in which Munc18-1 is replaced by a mutated form of Munc18-1 that cannot be phosphorylated. The main finding is that most PTP at hippocampal CA3 to CA1 synapses, or at cerebellar granule cell to Purkinje cell synapses does not rely on PKC phosphorylation of Munc18-1. Thus, mechanisms independent of PKC phosphorylation of Munc18-1 are important mediators of PTP.

neuroscience↗

bioRxiv2020

Cerebellar Activation Bidirectionally Regulates Nucleus Accumbens Shell and Core

Although the cerebellum is now recognized as part of a long-range brain network that serves limbic functions and motivated behavior, knowledge of cerebello-limbic connectivity is limited, and nothing is known about how the cerebellum connects functionally to the nucleus accumbens (NAc). Here, we report that stimulation of cerebellar nuclei in mice of both sexes modulates spiking activity in both NAc core and medial shell with fast excitation and slower, less synchronized inhibition. Fast responses would be well poised to support rapid communication of information critical to the control of motivated behavior, whereas slower responses may be suggestive of a regulatory function, such as gain control. Tracing experiments to chart cerebellar nuclei-NAc pathways identified disynaptic pathways that recruit the ventral tegmental area (VTA) and intralaminar thalamus (Centromedial and Parafascicular nuclei) as intermediary nodes. Optogenetic activation of cerebellar axons in each of these nodes was sufficient to evoke responses in both NAc core and medial shell, albeit with distinct, node-dependent properties. These pathways and the functional connectivity they support could underlie the role of the cerebellum in motivated behavior.

neuroscience↗

bioRxiv2020

High-frequency stimulation of ventral CA1 neurons reduces amygdala activity and inhibits fear

The hippocampus can be divided into distinct segments that make unique contributions to learning and memory. The dorsal hippocampus supports cognitive processes like spatial learning and navigation while the ventral hippocampus regulates emotional behaviors related to fear, anxiety and reward. In the current study, we determined how pyramidal cells in ventral CA1 respond to spatial cues and aversive stimulation during a context fear conditioning task. We also examined the effects of high and low frequency stimulation of these neurons on defensive behaviors. Similar to previous work in the dorsal hippocampus, we found that cells in ventral CA1 expressed high-levels of c-Fos in response to a novel spatial environment. Surprisingly, however, the number of activated neurons did not increase when the environment was subsequently paired with footshock. This was true even in the subpopulation of ventral CA1 pyramidal cells that send direct projections to the amygdala. When these cells were stimulated at high-frequencies (20-Hz), we observed feedforward inhibition of basal amygdala neurons and impaired expression of context fear. In contrast, low-frequency stimulation (4-Hz) did not inhibit principal cells in the amygdala and produced a slight increase in fear generalization. Similar results have been reported in dorsal CA1. Therefore, despite the clear differences between the dorsal and ventral hippocampus, CA1 neurons in each segment appear to make similar contributions to context fear conditioning.

neuroscience↗