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Understanding percepts, engrams and actions requires methods for selectively modulating synaptic communication between specific subsets of interconnected cells. Here, we develop an approach to control synaptically connected elements using bioluminescent light: Luciferase-generated light, originating from a presynaptic axon terminal, modulates an opsin in its postsynaptic target. Vesicular-localized luciferase is released into the synaptic cleft in response to presynaptic activity, creating a real-time Optical Synapse. Light production is under experimenter-control by introduction of the small molecule luciferin. Signal transmission across this optical synapse is temporally defined by the presence of both the luciferin and presynaptic activity. We validate synaptic Interluminescence by multi-electrode recording in cultured neurons and in mice in vivo. Interluminescence represents a powerful approach to achieve synapse-specific and activity-dependent circuit control in vivo., Prakash et al. develop an approach to control synaptically connected elements using bioluminescent light, in which Luciferase-generated light, originating from a presynaptic axon terminal, modulates an opsin in its postsynaptic target to form an ‘optical synapse’. They validate their optical synapses in cultured neurons and in mice in vivo and show that they provide an approach to achieve synapse-specific and activity-dependent circuit control in vivo.

The peripheral trigeminovascular pathway mediates orofacial and craniofacial pain and projects centrally to the brainstem trigeminal nucleus caudalis (TNc). Sensitization of this pathway is involved in many pain conditions, but little is known about synaptic plasticity at its first central synapse. We have taken advantage of optogenetics to investigate plasticity selectively evoked at synapses of nociceptive primary afferents onto TNc neurons. Based on immunolabeling in the trigeminal ganglia, TRPV1-lineage neurons comprise primarily peptidergic and nonpeptidergic nociceptors. Optical stimulation of channelrhodopsin-expressing axons in the TRPV1/ChR2 mouse in TNc slices thus allowed us to activate a nociceptor-enriched subset of primary afferents. We recorded from lamina I/II neurons in acutely prepared transverse TNc slices, and alternately stimulated two independent afferent pathways, one with light-activated nociceptive afferents and the other with electrically-activated inputs. Low-frequency optical stimulation induced robust long-term depression (LTD) of optically-evoked EPSCs, but not of electrically-evoked EPSCs in the same neurons. Blocking NMDA receptors or nitric oxide synthase strongly attenuated LTD, whereas a cannabinoid receptor 1 antagonist had no effect. The neuropeptide PACAP-38 or the nitric oxide donors nitroglycerin or sodium nitroprusside are pharmacologic triggers of human headache. Bath application of any of these three compounds also persistently depressed optically-evoked EPSCs. Together, our data show that LTD of nociceptive afferent synapses on trigeminal nucleus neurons is elicited when the afferents are activated at frequencies consistent with the development of central sensitization of the trigeminovascular pathway. SIGNIFICANCE STATEMENT Animal models suggest that sensitization of trigeminovascular afferents plays a major role in craniofacial pain syndromes including primary headaches and trigeminal neuralgia, yet little is known about synaptic transmission and plasticity in the brainstem trigeminal nucleus caudalis (TNc). Here we used optogenetics to selectively drive a nociceptor-enriched population of trigeminal afferents while recording from superficial laminae neurons in the TNc. Low-frequency optical stimulation evoked robust long-term depression at TRPV1/ChR2 synapses. Moreover, application of three different headache trigger drugs also depressed TRPV1/ChR2 synapses. Synaptic depression at these primary afferent synapses may represent a newly identified mechanism contributing to central sensitization during headache.

Summary The ventral tegmental area (VTA) is a major target of addictive drugs and receives multiple GABAergic projections originating outside the VTA. We describe differences in synaptic plasticity and behavior when optogenetically driving two opiate-sensitive GABAergic inputs to the VTA, the rostromedial tegmental nucleus (RMTg), and the periaqueductal gray (PAG). Activation of GABAergic RMTg terminals in the VTA in vivo is aversive, and low-frequency stimulation induces long-term depression in vitro. Low-frequency stimulation of PAG afferents in vitro unexpectedly causes long-term potentiation. Opioid receptor activation profoundly depresses PAG and RMTg inhibitory synapses but prevents synaptic plasticity only at PAG synapses. Activation of the GABAergic PAG terminals in the VTA promotes immobility, and optogenetically-driven immobility is blocked by morphine. Our data reveal the PAG as a source of highly opioid-sensitive GABAergic afferents and support the idea that different GABAergic pathways to the VTA control distinct behaviors.

The objective of this investigation is to study how excess body weight influences the energy cost of walking (Cw) and determine whether overweight and obese older adults self-select stride frequency to minimize Cw.Using body mass index (BMI), men and women between the ages of 65 and 80 yr were separated into normal weight (NW, BMI ≤24.9 kg·m(-2), n = 13) and overweight-obese groups (OWOB, BMI ≥25.0 kg·m(-2), n = 13). Subjects walked at 0.83 m·s on an instrumented treadmill that recorded gait parameters and completed three 6-min walking trials; at a preferred stride frequency (PSF), at +10% PSF, and at -10% PSF. Cw was determined by indirect calorimetry. Repeated-measures ANOVA was used to compare groups, and associations were tested with Pearson correlations, α = 0.05.OWOB had 62% greater absolute Cw (301 ± 108 vs 186 ± 104 J·m, P0.001) and 20% greater relative Cw(kg) (3.48 ± 0.95 vs 2.91 ± 0.94 J·kg(-1)·m(-1), P = 0.046) than NW. Although PSF was not different between OWOB and NW (P = 0.626), Cw was 8% greater in OWOB at +10% PSF (P0.001). At PSF, OWOB spent less time in single-limb support (33.1% ± 1.5% vs. 34.9% ± 1.6 % gait cycle, P = 0.021) and more time in double-limb support (17.5% ± 1.6% vs 15.4% ± 1.4% gait cycle, P = 0.026) than NW. In OWOB, at PSF, Cw was correlated to impulse (r = -0.57, P = 0.027) and stride frequency (r = 0.51, P = 0.046).Excess body weight is associated with greater Cw in older adults, possibly contributing to reduced mobility in overweight and obese older persons.

Drug exposure induces cell and synaptic plasticity within the brain reward pathway that could be a catalyst for progression to addiction. Several cellular adaptations have been described in the ventral tegmental area (VTA), a central component of the reward pathway that is the major source of dopamine release. For example, administration of morphine induces long-term potentiation (LTP) of excitatory synapses on VTA dopamine cells and blocks LTP at inhibitory synapses. Drug-induced synaptic changes have a common endpoint of increasing dopamine cell firing and dopamine release. However, gaining a complete picture of synaptic plasticity in the VTA is hindered by its complex circuitry of efferents and afferents. Most studies of synaptic plasticity in the VTA activated a mixed population of afferents, potentially yielding an incomplete and perhaps misleading view of how drugs of abuse modify VTA synapses. Here, we use midbrain slices from mice and find that electrical stimulation in two different regions induces different forms of plasticity, including two new forms of LTP at inhibitory synapses. High frequency stimulation induces LTP independently of NMDA receptor activation, and surprisingly, some inhibitory inputs to the VTA also undergo NMDAR-independent LTP after a low frequency stimulation (LFS) pairing protocol. SIGNIFICANCE STATEMENT Synaptic plasticity of inhibitory inputs onto dopamine cells in the ventral tegmental area has a major influence on the circuits implicated in addictive behaviors. The location of electrical stimulation in an acute midbrain slice dictatedthe response of inhibitory inputs to plasticity induction protocols. We describe a new form of synaptic strengthening that occurs at an opioid-sensitive input to the ventral tegmental area.

Background Recent evidence implicates toll-like receptor 4 (TLR4) in opioid analgesia, tolerance, conditioned place preference, and self-administration. Here, we determined the effect of the TLR4 antagonist (+)-naltrexone (a μ-opioid receptor inactive isomer) on the time-dependent increases in cue-induced heroin seeking after withdrawal (incubation of heroin craving). Methods In an initial experiment, we trained rats for 9 hours per day to self-administer heroin (.1 mg/kg/infusion) for 9 days; lever presses were paired with a 5-second tone-light cue. We then assessed cue-induced heroin seeking in 30-minute extinction sessions on withdrawal day 1; immediately after testing, we surgically implanted rats with Alzet minipumps delivering (+)-naltrexone (0, 7.5, 15, 30 mg/kg/day, subcutaneous) for 14 days. We then tested the rats for incubated cue-induced heroin seeking in 3-hour extinction tests on withdrawal day 13. Results We found that chronic delivery of (+)-naltrexone via minipumps during the withdrawal phase decreased incubated cue-induced heroin seeking. In follow-up experiments, we found that acute injections of (+)-naltrexone immediately before withdrawal day 13 extinction tests had no effect on incubated cue-induced heroin seeking. Furthermore, chronic delivery of (+)-naltrexone (15 or 30 mg/kg/day) or acute systemic injections (15 or 30 mg/kg) had no effect on ongoing extended access heroin self-administration. Finally, in rats trained to self-administer methamphetamine (.1 mg/kg/infusion, 9 hours/day, 9 days), chronic delivery of (+)-naltrexone (30 mg/kg/day) during the withdrawal phase had no effect on incubated cue-induced methamphetamine seeking. Conclusions The present results suggest a critical role of TLR4 in the development of incubation of heroin, but not methamphetamine, craving.

Rationale and objective: In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. We previously demonstrated that the projections from ventral medial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) shell play a role in this reinstatement. The ventral subiculum (vSub) sends glutamate projections to NAc shell and vmPFC. Here, we determined whether these projections contribute to context-induced reinstatement. Methods: We trained rats to self-administer heroin (0.05–0.1 mg/kg/infusion) for 3 h per day for 12 days; drug infusions were paired with a discrete tone–light cue. Lever pressing in the presence of the discrete cue was subsequently extinguished in a different context. We then tested the rats for reinstatement in the heroin- and extinction-associated contexts under extinction conditions. We combined Fos with the retrograde tracer Fluoro-Gold (FG) to determine projection-specific activation during the context-induced reinstatement tests. We also used anatomical disconnection procedures to determine whether the vSub → NAc shell and vSub → vmPFC projections are functionally involved in this reinstatement. Results: Exposure to the heroin but not the extinction context reinstated lever pressing. Context-induced reinstatement of heroin seeking was associated with increased Fos expression in vSub neurons, including those projecting to NAc shell and vmPFC. Anatomical disconnection of the vSub → NAc shell projection, but not the vSub → vmPFC projection, decreased this reinstatement. Conclusions: Our data indicate that the vSub → NAc shell glutamatergic projection, but not the vSub → vmPFC projection, contributes to context-induced reinstatement of heroin seeking.

We developed recently a binge-eating model in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after 15 min exposure to the sight of the palatable food. This “frustration stress” manipulation also activates the hypothalamic–pituitary–adrenal stress axis. Here, we determined the role of the stress neurohormone corticotropin-releasing factor (CRF) in stress-induced binge eating in our model. We also assessed the role of CRF receptors in the bed nucleus of the stria terminalis (BNST), a brain region implicated in stress responses and stress-induced drug seeking, in stress-induced binge eating. We used four groups that were first exposed or not exposed to repeated intermittent cycles of regular chow food restriction during which they were also given intermittent access to high-caloric palatable food. On the test day, we either exposed or did not expose the rats to the sight of the palatable food for 15 min (frustration stress) before assessing food consumption for 2 h. We found that systemic injections of the CRF1 receptor antagonist R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7 dipropylamino pyrazolo[1,5-a]pyrimidine) (10–20 mg/kg) and BNST (25–50 ng/side) or ventricular (1000 ng) injections of the nonselective CRF receptor antagonistd-Phe-CRF(12–41)decreased frustration stress-induced binge eating in rats with a history of food restriction. Frustration stress also increased Fos (a neuronal activity marker) expression in ventral and dorsal BNST. Results demonstrate a critical role of CRF receptors in BNST in stress-induced binge eating in our rat model. CRF1 receptor antagonists may represent a novel pharmacological treatment for bingeing-related eating disorders.

Cocaine generates drug-seeking behavior by creating long-lasting changes in the reward pathway. The role of the growth factor, brain-derived neurotrophic factor (BDNF) in facilitating these changes was investigated in the present report with a genetic rat model. Using conditioned place preference, the current study investigated the hypothesis that a partial knockout of the BDNF gene in rats (BDNF(+/-)) would attenuate the rewarding effects of cocaine. Wildtype rats exposed to cocaine exhibited normal cocaine-seeking responses one day after conditioning and cocaine-seeking behavior was reinstated with drug priming following drug abstinence. In contrast, BDNF(+/-) rats did not show cocaine-seeking behavior one day after conditioning, nor did they respond to drug priming. A median split of rats based on BDNF levels in sera collected prior to behavioral procedures revealed that wildtype rats with high BDNF levels showed stronger conditioned place preference and reinstatement to cocaine. Together, the results support the hypothesis that a partial knockout of the BDNF gene attenuates the rewarding properties of cocaine. Additionally, individual differences in BDNF levels may predict future cocaine-seeking behavior. An underlying mechanism of these effects may be a reduction of the amount of synaptic changes made in the reward pathway.