key: cord-0685380-9ignuler authors: Asp, Anders J.; Boschen, Suelen Lucio; Lujan, J. Luis title: An ultra-low frequency spike timing dependent plasticity-based approach for treating alcohol use disorder date: 2021-09-20 journal: bioRxiv DOI: 10.1101/2021.09.16.460673 sha: b5a0c4683ea012b96b5b787eaabe7387d8a04f1f doc_id: 685380 cord_uid: 9ignuler Alcohol use disorder (AUD) is a chronic relapsing brain disorder characterized by an impaired ability to stop or control alcohol consumption despite adverse social, occupational, or health consequences. AUD affects nearly one-third of adults at some point during their lives, with an associated cost of approximately $249 billion annually in the U.S. alone. The effects of alcohol consumption are expected to increase significantly during the COVID-19 pandemic, with alcohol sales increased by approximately 54%, potentially exacerbating health concerns and risk-taking behaviors. Unfortunately, existing pharmacological and behavioral therapies for AUD have historically been associated with poor success rates, with approximately 40% of individuals relapsing within three years of treatment. Pre-clinical studies have shown that chronic alcohol consumption leads to significant changes in synaptic function within the dorsal medial striatum (DMS), one of the brain regions associated with AUD and responsible for mediating goal-directed behavior. Specifically, chronic alcohol consumption has been associated with hyperactivity of dopamine receptor 1 (D1) medium spiny neurons (MSN) and hypoactivity of dopamine receptor 2 (D1) MSNs within the DMS. Optogenetic, chemogenetic, and transgenic approaches have demonstrated that reducing the D1/D2 MSN signaling imbalance decreases alcohol self-administration in rodent models of AUD. However, these approaches cannot be studied clinically at this time. Here, we present an electrical stimulation alternative that uses ultra-low (<=1Hz) frequency (ULF) spike-timing dependent plasticity (STDP) to reduce DMS D1/D2 MSN signaling imbalances by stimulating D1-MSN afferents into the GPi and ACC glutamatergic projections to the DMS in a time-locked stimulation sequence. Our data suggest that GPi/ACC ULF-STDP selectively decreases DMS D1-MSN hyperactivity leading to reduced alcohol consumption without evoking undesired affective behaviors in a two-bottle choice mouse model of AUD. receives cortical glutamatergic input from limbic regions, such as the medial prefrontal cortex and anterior cingulate cortex (ACC) 34, 35 . The DMS contains two neuronal types: 1) Dopamine receptor 1-medium spiny neurons (D1-MSNs) and 2) Dopamine receptor 2-medium spiny neurons (D2-MSNs). D1-MSNs project to the internal Globus Pallidus (GPi) through the direct pathway and their activation results in a 'go' signal to initiate behavior [36] [37] [38] [39] [40] . In contrast, D2-MSNs project to the external Globus Pallidus (GPe) through the indirect pathway and their activation serves as a 'stop' signal to inhibit behavior [36] [37] [38] [39] [40] . Chronic alcohol consumption has been shown to cause permanent hyperactivity of D1-MSNs and permanent hypoactivity of D2-MSNs in the DMS via maladaptive cortical glutamatergic signaling from areas such as the ACC [13] [14] [15] [16] [17] . Studies have shown that reducing the ratio of DMS D1-MSN/D2-MSN signaling imbalance reduces pathological alcohol seeking behavior 17, [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] . Furthermore, a recent report demonstrated that inducing long-term depression (LTD) by applying a single 10minute epoch of low frequency (1Hz) optogenetic stimulation of ACC projections to the DMS, combined with systemic D1-dopamine receptor antagonism, leads to a reduction in alcohol consumption lasting for nine days 26 . Data suggest that deep brain stimulation (DBS), an increasingly prevalent therapy for motor and psychiatric disorders 41-44 6,7,11,45-48 49 , may offer therapeutic effects for the treatment of AUD 4,6-10 . However, unlike DBS for movement disorders, there is an absence of markers of DBS efficacy for the treatment of addiction and other psychiatric conditions 50, 51 , leading to challenging selection of surgical targets and stimulation parameters. These factors, combined with nonspecific network effects of DBS 52 , can lead to undesirable side effects and highly variable outcomes in the treatment of addiction-related behaviors such as AUD 5, 11, 53, 54 . Thus, re-imagining the way that DBS is administered may lead to the development of new therapeutic interventions for a wide range of neuropsychiatric and neurologic disorders. Here, we leverage neuroplasticity induction protocols capable of selectively reversing the pathophysiology underlying neuropsychiatric conditions such as AUD. 30, [55] [56] [57] . Changes in synaptic strength are evoked by leveraging spike-timing dependent plasticity (STDP) 30 where an electrical stimulus is applied to cortical axons C1/C2 within a temporal window with respect to stimulation of postsynaptic axons D1/D2 (D). In this example, orthodromic action potential propagation from ACC axons and antidromic action potential propagation from D1 axons in GPi will converge to alter the gain of the spatially unique synapse (C1-D1) while gain of synapses out of this network are unchanged. This protocol is repeated at ≤1Hz for 10 minutes. to food and water. Animals were acclimated for at least one weeks before use. All efforts were made to minimize both the number of mice used and any discomfort that may be experienced. Stereotactic surgery: All animals were induced at 4% isoflurane and maintained at 1-2% through a nose cone for the duration of the surgery. The depth of anesthesia was monitored using toe pinch and eye blink reflexes. A heating pad was used to maintain the subject's body temperature to 37.0±0.5 ºC throughout the duration of anesthesia. Analgesia was provided with buprenorphine HCL (0.05 mg/kg). Additionally, Ibuprofen was delivered in the animals' drinking water two days prior to the surgery and no less than five days after for analgesia. Animals were monitored twice daily for five days following surgery for signs of distress and infection at the surgical site. If signs of infection or distress were observed, topical polysporin antibacterial ointment was applied to the surgical site or a veterinarian was consulted for the appropriate methods of treatment. Sil silicone elastomer (World Precision Instruments, Sarasota, FL, USA) was put around the Zif-Clip microwire array and stimulating electrodes to maintain a seal between the brain and dental cement described in the next step. Finally, all components were secured with Metabond dental cement (Parkell, Edgewood, NY, USA). After the electrode implantation surgery, the animals were housed individually for one week to allow sufficient time for recovery. A standard two-bottle choice paradigm was used to assess alcohol consumption 63 . Briefly, two bottles were presented daily: one containing water and the other alcohol 64 . The position of the alcohol and water bottles was swapped daily to reduce confounds produced by location preference. For the first week, alcohol concentrations were increased every other day from 3% to 6% to 10% v/v. For the remaining duration of the experiment, mice were presented with one bottle of water and another bottle with 10% alcohol. For three alcohol exposure days prior to ULF-STDP delivery, the animals were tethered to the stimulating system to allow habituation to the procedure. At day 25, animals were stimulated with the ULF-STDP protocol described in the methods section under Electrical stimulation parameters if mean and standard error of alcohol consumption (calculated in g/kg of body mass at be beginning of the night cycle) was less than 20% over a 3-day period after at least two weeks of alcohol exposure. The mass of each mouse, the mass of alcohol consumed, and the mass of water consumed was assessed daily. Additionally, an IR beam break sensor was placed in front of the sippers to measure the total time spent interacting with the sipper. Figure S1 ). Additionally, there were no differences in spectral band power before and after ULF-STDP ( Figure S2 ). Latency from stimulation to peak evoked multiunit response did not differ between stimulation location and was not affected by ULF-STDP(+) ( Figure 5D ). (Figures 6B, C) , but not the frequency ( Figure 6D, E) (ULF-STDP(+) n=1 mouse, n=3 cells; naiive n=5 mice, n=1-3 cells/mouse, p<0.05). Here, we describe a novel approach for using STDP (spike-timing dependent plasticity) to reverse maladaptive hyperactivity of DMS D1-MSNs associated with AUD alcohol use disorder. This approach relies upon a method of delivering Conversely, it has also been repeatedly demonstrated that in the corticostriatal synapse, presynaptic depolarization prior to postsynaptic depolarization causes LTD 68, 69 . While our STDP findings may appear to disagree with prior studies, there are important methodological differences which explain these seemingly contradictory results. Namely, in Figure 3 , ULF-STDP is delivered while the animal is awake and during a state of acute withdrawal. 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Box and whisker plots in B-C represent median, 95% CI, and max/minimum where black dots and gray lines represent individual animals. S2: Microwire array impedances measured via TDT PZ5 neurodigitizer amplifier. Data are displayed as mean with error bars representing standard error of impedance values of all electrodes for S3: Local field potential band power analysis showing representative power spectral density(A) and spectrogram (B) before and after ULF-STDP (+)