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Transcranial focused ultrasound (tFUS) neuromodulation provides a promising emerging non-invasive therapy for the treatment of neurological disorders. Many studies have demonstrated the ability of tFUS to elicit transient changes in neural responses. However, the ability of tFUS to induce sustained changes need to be carefully examined. In this study, we use the long-term potentiation/long term depression (LTP/LTD) model in the rat hippocampus, the medial perforant path (mPP) to dentate gyrus (DG) pathway, to explore whether tFUS is capable of encoding frequency specific information to induce plasticity. Single-element focused transducers were used for tFUS stimulation with ultrasound fundamental frequency of 0.5 MHz and nominal focal distance of 38 mm tFUS stimulation is directed to mPP. Measurement of synaptic connectivity is achieved through the slope of field excitatory post synaptic potentials (fEPSPs), which are elicited using bipolar electrical stimulation electrodes and recorded at DG using extracellular electrodes to quantify degree of plasticity. We applied pulsed tFUS stimulation with total duration of 5 min, with 5 levels of pulse repetition frequencies each administered at 50 Hz sonication frequency at the mPP. Baseline fEPSP is recorded 10 min prior, and 30+ minutes after tFUS administration. In N = 16 adult wildtype rats, we observed sustained depression of fEPSP slope after 5 min of tFUS focused at the presynaptic field mPP. Across all PRFs, no significant difference in maximum fEPSP slope change was observed, average tFUS induced depression level was observed at 19.6%. When compared to low frequency electrical stimulation (LFS) of 1 Hz delivered to the mPP, the sustained changes induced by tFUS stimulation show no statistical difference to LFS for up to 24 min after tFUS stimulation. When both the maximum depression effects and the duration of sustained effects are both taken into account, PRF 3 kHz can induce significantly larger effects than other PRFs tested. tFUS stimulation is measured with a spatial-peak pressure amplitude of 99 kPa, translating to an estimation of 0.43 °C temperature increase when assuming no loss of heat. The results suggest the ability of tFUS to encode sustained changes in synaptic connectivity through mechanism which are unlikely to involve thermal changes.

Transcranial focused ultrasound (tFUS) neuromodulation provides a promising emerging non-invasive therapy for the treatment of neurological disorders. Many studies have demonstrated the ability of tFUS to elicit transient changes in neural responses. However, the ability of tFUS to induce sustained changes need to be carefully examined. In this study, we use the long-term potentiation/long term depression (LTP/LTD) model in the rat hippocampus, the medial perforant path (mPP) to dentate gyrus (DG) pathway, to explore whether tFUS is capable of encoding frequency specific information to induce plasticity. Single-element focused transducers were used for tFUS stimulation with ultrasound fundamental frequency of 0.5 MHz and nominal focal distance of 38 mm tFUS stimulation is directed to mPP. Measurement of synaptic connectivity is achieved through the slope of field excitatory post synaptic potentials (fEPSPs), which are elicited using bipolar electrical stimulation electrodes and recorded at DG using extracellular electrodes to quantify degree of plasticity. We applied pulsed tFUS stimulation with total duration of 5 min, with 5 levels of pulse repetition frequencies each administered at 50 Hz sonication frequency at the mPP. Baseline fEPSP is recorded 10 min prior, and 30+ minutes after tFUS administration. In N = 16 adult wildtype rats, we observed sustained depression of fEPSP slope after 5 min of tFUS focused at the presynaptic field mPP. Across all PRFs, no significant difference in maximum fEPSP slope change was observed, average tFUS induced depression level was observed at 19.6%. When compared to low frequency electrical stimulation (LFS) of 1 Hz delivered to the mPP, the sustained changes induced by tFUS stimulation show no statistical difference to LFS for up to 24 min after tFUS stimulation. When both the maximum depression effects and the duration of sustained effects are both taken into account, PRF 3 kHz can induce significantly larger effects than other PRFs tested. tFUS stimulation is measured with a spatial-peak pressure amplitude of 99 kPa, translating to an estimation of 0.43 °C temperature increase when assuming no loss of heat. The results suggest the ability of tFUS to encode sustained changes in synaptic connectivity through mechanism which are unlikely to involve thermal changes. • Low intensity tFUS neuromodulation applied for 5 min to the hippocampus can induce long term depression in in vivo rat models. • Intracranial recordings of field excitatory post synaptic potentials (fEPSP) show decreased slope after tFUS. • When compared to sham, tFUS can significantly induce sustained decrease in the hippocampal fEPSP slope. [ABSTRACT FROM AUTHOR]

Loss of function mutations in PARK6, the gene that encodes the protein PTEN-induced kinase 1 (PINK1), cause autosomal recessive familial Parkinson’s disease (PD). While PD is clinically diagnosed by its motor symptoms, recent studies point to the impact of non-motor symptoms, including cognitive dysfunction in the early pre-motor stages of the disease (Aarsland et al., 2004; Chaudhuri and Schapira, 2009). As the hippocampus is a key structure for learning and memory, this study aimed to determine whether synaptic transmission is affected at CA3-CA1 excitatory synapses in PINK1 knockout rats at an age when we recently reported a gain of function at excitatory synapses onto spiny projection neurons in the dorsal striatum (Creed et al., 2020) and when motor symptoms are beginning to appear (Dave et al., 2014). Using extracellular dendritic field excitatory postsynaptic potential recordings at CA3-CA1 synapses in dorsal hippocampus 4-to 5- month old PINK1 KO rats and wild-type littermate controls, we observed no detectable differences in the strength of basal synaptic transmission, paired-pulse facilitation, or long-term potentiation. Our results suggest that loss of PINK1 protein does not cause a general dysfunction of excitatory transmission throughout the brain at this young adult age when excitatory transmission is abnormal in the striatum.

Loss of function mutations in PARK6, the gene that encodes the protein PTEN-induced kinase 1 (PINK1), cause autosomal recessive familial Parkinson's disease (PD). While PD is clinically diagnosed by its motor symptoms, recent studies point to the impact of non-motor symptoms, including cognitive dysfunction in the early pre-motor stages of the disease (Aarsland et al., 2004; Chaudhuri and Schapira, 2009). As the hippocampus is a key structure for learning and memory, this study aimed to determine whether synaptic transmission is affected at CA3-CA1 excitatory synapses in PINK1 knockout rats at an age when we recently reported a gain of function at excitatory synapses onto spiny projection neurons in the dorsal striatum (Creed et al., 2020) and when motor symptoms are beginning to appear (Dave et al., 2014). Using extracellular dendritic field excitatory postsynaptic potential recordings at CA3-CA1 synapses in dorsal hippocampus 4-to 5- month old PINK1 KO rats and wild-type littermate controls, we observed no detectable differences in the strength of basal synaptic transmission, paired-pulse facilitation, or long-term potentiation. Our results suggest that loss of PINK1 protein does not cause a general dysfunction of excitatory transmission throughout the brain at this young adult age when excitatory transmission is abnormal in the striatum. [ABSTRACT FROM AUTHOR]

• Proton gated ASIC1a contribute to anterior cingulate cortex (ACC) synaptic currents. • ASIC1a synaptic currents at ACC are enhanced by corticosterone and histamine. • ASIC1a participate in the induction of glutamatergic synaptic currents LTP at ACC. • Histamine and corticosterone facilitate LTP induction at ACC. Increase in proton concentration [H+] or decrease in local and global extracellular pH occurs in both physiological and pathological conditions. Acid-sensing ion channels (ASICs), belonging to the ENaC/Deg superfamily, play an important role in signal transduction as proton sensor. ASICs and in particular ASIC1a (one of the six ASICs subunits) which is permeable to Ca2+, are involved in many physiological processes including synaptic plasticity and neurodegenerative diseases. Activity-dependent long-term potentiation (LTP) is a major type of long-lasting synaptic plasticity in the CNS, associated with learning, memory, development, fear and persistent pain. Neurons in the anterior cingulate cortex (ACC) play critical roles in pain perception and chronic pain and express ASIC1a channels. During synaptic transmission, acidification of the synaptic cleft presumably due to the co-release of neurotransmitter and H+ from synaptic vesicles activates postsynaptic ASIC1a channels in ACC of mice. This generates ASIC1a synaptic currents that add to the glutamatergic excitatory postsynaptic currents (EPSCs). Here we report that modulators like histamine and corticosterone, acting through ASIC1a regulate synaptic plasticity, reducing the threshold for LTP induction of glutamatergic EPSCs. Our findings suggest a new role for ASIC1a mediating the neuromodulator action of histamine and corticosterone regulating specific forms of synaptic plasticity in the mouse ACC. [ABSTRACT FROM AUTHOR]

The cerebellum plays a crucial role in motor learning and it acts as a predictive controller. Modeling it and embedding it into sensorimotor tasks allows us to create functional links between plasticity mechanisms, neural circuits and behavioral learning. Moreover, if applied to real-time control of a neurorobot, the cerebellar model has to deal with a real noisy and changing environment, thus showing its robustness and effectiveness in learning. A biologically inspired cerebellar model with distributed plasticity, both at cortical and nuclear sites, has been used. Two cerebellum-mediated paradigms have been designed: an associative Pavlovian task and a vestibulo-ocular reflex, with multiple sessions of acquisition and extinction and with different stimuli and perturbation patterns. The cerebellar controller succeeded to generate conditioned responses and finely tuned eye movement compensation, thus reproducing human-like behaviors. Through a productive plasticity transfer from cortical to nuclear sites, the distributed cerebellar controller showed in both tasks the capability to optimize learning on multiple time-scales, to store motor memory and to effectively adapt to dynamic ranges of stimuli.

Neuronal circuits can learn and replay firing patterns evoked by sequences of sensory stimuli. After training, a brief cue can trigger a spatiotemporal pattern of neural activity similar to that evoked by a learned stimulus sequence. Network models show that such sequence learning can occur through the shaping of feedforward excitatory connectivity via long term plasticity. Previous models describe how event order can be learned, but they typically do not explain how precise timing can be recalled. We propose a mechanism for learning both the order and precise timing of event sequences. In our recurrent network model, long term plasticity leads to the learning of the sequence, while short term facilitation enables temporally precise replay of events. Learned synaptic weights between populations determine the time necessary for one population to activate another. Long term plasticity adjusts these weights so that the trained event times are matched during playback. While we chose short term facilitation as a time-tracking process, we also demonstrate that other mechanisms, such as spike rate adaptation, can fulfill this role. We also analyze the impact of trial-to-trial variability, showing how observational errors as well as neuronal noise result in variability in learned event times. The dynamics of the playback process determines how stochasticity is inherited in learned sequence timings. Future experiments that characterize such variability can therefore shed light on the neural mechanisms of sequence learning. [ABSTRACT FROM AUTHOR]

The cerebellum plays a crucial role in motor learning and it acts as a predictive controller. Modeling it and embedding it into sensorimotor tasks allows us to create functional links between plasticity mechanisms, neural circuits and behavioral learning. Moreover, if applied to real-time control of a neurorobot, the cerebellar model has to deal with a real noisy and changing environment, thus showing its robustness and effectiveness in learning. A biologically inspired cerebellar model with distributed plasticity, both at cortical and nuclear sites, has been used. Two cerebellum-mediated paradigms have been designed: an associative Pavlovian task and a vestibulo-ocular reflex, with multiple sessions of acquisition and extinction and with different stimuli and perturbation patterns. The cerebellar controller succeeded to generate conditioned responses and finely tuned eye movement compensation, thus reproducing human-like behaviors. Through a productive plasticity transfer from cortical to nuclear sites, the distributed cerebellar controller showed in both tasks the capability to optimize learning on multiple time-scales, to store motor memory and to effectively adapt to dynamic ranges of stimuli. [ABSTRACT FROM AUTHOR]

How learning and memory is achieved in the brain is a central question in neuroscience. Key to today's research into information storage in the brain is the concept of synaptic plasticity, a notion that has been heavily influenced by Hebb's (1949) postulate. Hebb conjectured that repeatedly and persistently co-active cells should increase connective strength among populations of interconnected neurons as a means of storing a memory trace, also known as an engram. Hebb certainly was not the first to make such a conjecture, as we show in this history. Nevertheless, literally thousands of studies into the classical frequency-dependent paradigm of cellular learning rules were directly inspired by the Hebbian postulate. But in more recent years, a novel concept in cellular learning has emerged, where temporal order instead of frequency is emphasized. This new learning paradigm - known as spike-timing-dependent plasticity (STDP) - has rapidly gained tremendous interest, perhaps because of its combination of elegant simplicity, biological plausibility, and computational power. But what are the roots of today's STDP concept? Here, we discuss several centuries of diverse thinking, beginning with philosophers such as Aristotle, Locke, and Ribot, traversing, e.g., Lugaro's plasticità and Rosenblatt's perceptron, and culminating with the discovery of STDP. We highlight interactions between theoretical and experimental fields, showing how discoveries sometimes occurred in parallel, seemingly without much knowledge of the other field, and sometimes via concrete back-and-forth communication. We point out where the future directions may lie, which includes interneuron STDP, the functional impact of STDP, its mechanisms and its neuromodulatory regulation, and the linking of STDP to the developmental formation and continuous plasticity of neuronal networks.