Disrupting Reconsolidation by Systemic Inhibition of mTOR Kinase via Rapamycin Reduces Cocaine-Seeking Behavior

Drug addiction is considered maladaptive learning, and drug-related memories aroused by the presence of drug related stimuli (drug context or drug-associated cues) promote recurring craving and reinstatement of drug seeking. The mammalian target of rapamycin signaling pathway is involved in reconsolidation of drug memories in conditioned place preference and alcohol self-administration (SA) paradigms. Here, we explored the effect of mTOR inhibition on reconsolidation of addiction memory using cocaine self-administration paradigm. Rats received intravenous cocaine self-administration training for 10 consecutive days, during which a light/tone conditioned stimulus was paired with each cocaine infusion. After acquisition of the stable cocaine self-administration behaviors, rats were subjected to nosepoke extinction (11 days) to extinguish their behaviors, and then received a 15 min retrieval trial with or without the cocaine-paired tone/light cue delivery or without. Immediately or 6 h after the retrieval trial, rapamycin (10 mg/kg) was administered intraperitoneally. Finally, cue-induced reinstatement, cocaine-priming-induced reinstatement and spontaneous recovery of cocaine-seeking behaviors were assessed in rapamycin previously treated animals, respectively. We found that rapamycin treatment immediately after a retrieval trial decreased subsequent reinstatement of cocaine seeking induced by cues or cocaine itself, and these effects lasted at least for 28 days. In contrast, delayed intraperitoneal injection of rapamycin 6 h after retrieval or rapamycin injection without retrieval had no effects on cocaine-seeking behaviors. These findings indicated that mTOR inhibition within the reconsolidation time-window impairs the reconsolidation of cocaine associated memory, reduces cocaine-seeking behavior and prevents relapse, and these effects are retrieval-dependent and temporal-specific.

Pairing vagus nerve stimulation with tones drives plasticity across the auditory pathway

Previous studies have demonstrated that pairing vagus nerve stimulation (VNS) with sounds can enhance the primary auditory cortex (A1) response to the paired sound. The neural response to sounds following VNS-sound pairing in other subcortical and cortical auditory fields has not been documented. We predicted that VNS-tone pairing would increase neural responses to the paired tone frequency across the auditory pathway. In this study, we paired VNS with the presentation of a 9-kHz tone 300 times a day for 20 days. We recorded neural responses to tones from 2,950 sites in the inferior colliculus (IC), A1, anterior auditory field (AAF), and posterior auditory field (PAF) 24 h after the last pairing session in anesthetized rats. We found that VNS-tone pairing increased the percentage of IC, A1, AAF, and PAF that responds to the paired tone frequency. Across all tested auditory fields, the response strength to tones was strengthened in VNS-tone paired rats compared with control rats. VNS-tone pairing reduced spontaneous activity, frequency selectivity, and response threshold across the auditory pathway. This is the first study to document both cortical and subcortical plasticity following VNS-sound pairing. Our findings suggest that VNS paired with sound presentation is an effective method to enhance auditory processing. NEW & NOTEWORTHY Previous studies have reported primary auditory cortex plasticity following vagus nerve stimulation (VNS) paired with a sound. This study extends previous findings by documenting that fields across the auditory pathway are altered by VNS-tone pairing. VNS-tone pairing increases the percentage of each field that responds to the paired tone frequency. This is the first study to document both cortical and subcortical plasticity following VNS-sound pairing.

Frequency tuning of synaptic inhibition underlying duration-tuned neurons in the mammalian inferior colliculus

Inhibition plays an important role in creating the temporal response properties of duration-tuned neurons (DTNs) in the mammalian inferior colliculus (IC). Neurophysiological and computational studies indicate that duration selectivity in the IC is created through the convergence of excitatory and inhibitory synaptic inputs offset in time. We used paired-tone stimulation and extracellular recording to measure the frequency tuning of the inhibition acting on DTNs in the IC of the big brown bat ( Eptesicus fuscus). We stimulated DTNs with pairs of tones differing in duration, onset time, and frequency. The onset time of a short, best-duration (BD), probe tone set to the best excitatory frequency (BEF) was varied relative to the onset of a longer-duration, nonexcitatory (NE) tone whose frequency was varied. When the NE tone frequency was near or within the cell’s excitatory bandwidth (eBW), BD tone-evoked spikes were suppressed by an onset-evoked inhibition. The onset of the spike suppression was independent of stimulus frequency, but both the offset and duration of the suppression decreased as the NE tone frequency departed from the BEF. We measured the inhibitory frequency response area, best inhibitory frequency (BIF), and inhibitory bandwidth (iBW) of each cell. We found that the BIF closely matched the BEF, but the iBW was broader and usually overlapped the eBW measured from the same cell. These data suggest that temporal selectivity of midbrain DTNs is created and preserved by having cells receive an onset-evoked, constant-latency, broadband inhibition that largely overlaps the cell’s excitatory receptive field. We conclude by discussing possible neural sources of the inhibition. NEW & NOTEWORTHY Duration-tuned neurons (DTNs) arise from temporally offset excitatory and inhibitory synaptic inputs. We used single-unit recording and paired-tone stimulation to measure the spectral tuning of the inhibitory inputs to DTNs. The onset of inhibition was independent of stimulus frequency; the offset and duration of inhibition systematically decreased as the stimulus departed from the cell’s best excitatory frequency. Best inhibitory frequencies matched best excitatory frequencies; however, inhibitory bandwidths were more broadly tuned than excitatory bandwidths.

The Pedunculopontine Tegmental Nucleus: A Second Cholinergic Source for Frequency-Specific Auditory Plasticity

Cholinergic modulation is essential for many brain functions and is an indispensable component of the prevalent models attempting to understand the neural mechanism responsible for learning-induced auditory plasticity. Unlike the cholinergic basal forebrain, the cholinergic pedunculopontine tegmental nucleus (PPTg) has received little attention. This study was designed to confirm whether the PPTg enables frequency-specific plasticity in the ventral division of the medial geniculate body of the thalamus (MGBv). Using the mouse model, we paired electrical stimulation of the PPTg with tone stimulation to help define the role of the PPTg. The receptive fields of MGBv neurons were examined before and after the paired stimulation; they were quantified in this study by best frequency (BF), response threshold, dynamic range, and spike number. We found that the electrical stimulation of the PPTg together with a tone presentation shifted the BFs of MGBv neurons upward when the frequency of the paired tone was higher than that of the control BF. Similarly, the BFs shifted downward when the frequency of the paired tone was lower than that of the control BF. The BFs of MGBv neurons, however, remained unchanged when the frequency of the paired tone was the same as that of the control BF. There was a linear relationship between the BF shift of MGBv neurons and the difference between the frequency of the paired tone and the control BF of MGBv neurons. Highly frequency specific changes were also observed in the response threshold, dynamic range, and spike number. This frequency-specific plasticity was largely eliminated by the microinjection of the muscarinic receptor antagonist atropine into the MGBv before the paired stimulation. Our findings suggest that the PPTg, like the cholinergic basal forebrain, is an important cholinergic source that enables frequency-specific plasticity in the central auditory system.