Suppressing fear in the presence of a safety cue requires infralimbic cortical signaling to central amygdala.

Stressful events can have lasting and impactful effects on behavior, especially by disrupting normal regulation of fear and reward processing. Accurate discrimination among environmental cues predicting threat, safety or reward adaptively guides behavior. Post-traumatic stress disorder (PTSD) represents a condition in which maladaptive fear persists in response to explicit safety-predictive cues that coincide with previously learned threat cues, but without threat being present. Since both the infralimbic cortex (IL) and amygdala have each been shown to be important for fear regulation to safety cues, we tested the necessity of specific IL projections to the basolateral amygdala (BLA) or central amygdala (CeA) during safety recall. Male Long Evans rats were used since prior work showed female Long Evans rats did not acquire the safety discrimination task used in this study. Here, we show the infralimbic projection to the central amygdala was necessary for suppressing fear cue-induced freezing in the presence of a learned safety cue, and the projection to the basolateral amygdala was not. The loss of discriminative fear regulation seen specifically during IL->CeA inhibition is similar to the behavioral disruption seen in PTSD individuals that fail to regulate fear in the presence of a safety cue.

Review of RM-1929 Near-Infrared Photoimmunotherapy Clinical Efficacy for Unresectable and/or Recurrent Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) contribute to a significant global cancer burden. Developments in current therapeutic approaches have improved patient outcomes but have limited efficacy in patients with unresectable and/or recurrent HNSCC. RM-1929 near-infrared photoimmunotherapy (NIR-PIT) is an emerging treatment that is currently being investigated in a Phase III clinical trial and has been conditionally approved for the treatment of unresectable and/or recurrent HNSCC in Japan. Here, we collect a series of case reports and clinical trial data to assess the efficacy of RM-1929 NIR-PIT. Disease control rates ranged from 66.7 to 100% across these studies, and overall response rates ranged from 43.3 to 100%, suggesting positive clinical outcomes. Low-grade postoperative localized pain and edema were the most frequently reported side effects, and preliminary reports on quality of life and pain levels suggest that RM-1929 NIR-PIT does not significantly decrease quality of life and is manageable with existing pain management strategies, including opioids. These preliminary data in real-world use of RM-1929 NIR-PIT show that it is a well-tolerated therapy that has clinically meaningful outcomes for patients with unresectable and/or recurrent HNSCC.

Orbitofrontal-striatal potentiation underlies cocaine-induced hyperactivity.

Psychomotor stimulants increase dopamine levels in the striatum and promote locomotion; however, their effects on striatal pathway function in vivo remain unclear. One model that has been proposed to account for these motor effects suggests that stimulants drive hyperactivity via activation and inhibition of direct and indirect pathway striatal neurons, respectively. Although this hypothesis is consistent with the cellular actions of dopamine receptors and received support from optogenetic and chemogenetic studies, it has been rarely tested with in vivo recordings. Here, we test this model and observe that cocaine increases the activity of both pathways in the striatum of awake mice. These changes are linked to a dopamine-dependent cocaine-induced strengthening of upstream orbitofrontal cortex (OFC) inputs to the dorsomedial striatum (DMS) in vivo. Finally, depressing OFC-DMS pathway with a high frequency stimulation protocol in awake mice over-powers the cocaine-induced potentiation of OFC-DMS pathway and attenuates the expression of locomotor sensitization, directly linking OFC-DMS potentiation to cocaine-induced hyperactivity.

Weight Loss After Obesity is Associated with Increased Food Motivation and Faster Weight Regain in Mice.

OBJECTIVE: While changes in diet often result in short-term weight loss, weight loss is not typically maintained. It remains unclear why long-term weight loss is so difficult. It was hypothesized that obesity produces persistent changes in behavior that bias animals toward weight regain after weight loss. METHODS: Mice were induced to gain weight with a high-fat diet for 6 weeks and then induced to lose this weight with a low-fat diet for 7 subsequent weeks. A control group was maintained on the low-fat diet for all 13 weeks. Activity was measured continuously with home cage activity monitors for the entire experiment. Motivation for sweetened food pellets was tested following weight loss. A separate group of mice was reexposed to a high-fat diet following 2, 4, or 8 weeks of withdrawal to assess the rate of weight regain. RESULTS: Activity levels decreased as animals gained weight and partially recovered following weight loss. Motivation for sucrose pellets was persistently heightened after weight loss. Consistent with these behavioral changes, mice also regained weight at a faster rate when reexposed to a high-fat diet after a period of weight loss. CONCLUSIONS: Weight loss after obesity was associated with increased motivation for palatable food and an increased rate of weight regain.

Continuous Representations of Speed by Striatal Medium Spiny Neurons.

The striatum is critical for controlling motor output. However, it remains unclear how striatal output neurons encode and facilitate movement. A prominent theory suggests that striatal units encode movements in bursts of activity near specific events, such as the start or end of actions. These bursts are theorized to gate or permit specific motor actions, thereby encoding and facilitating complex sequences of actions. An alternative theory has suggested that striatal neurons encode continuous changes in sensory or motor information with graded changes in firing rate. Supporting this theory, many striatal neurons exhibit such graded changes without bursting near specific actions. Here, we evaluated these two theories in the same recordings of mice (both male and female). We recorded single-unit and multiunit activity from the dorsomedial striatum of mice as they spontaneously explored an arena. We observed both types of encoding, although continuous encoding was more prevalent than bursting near movement initiation or termination. The majority of recorded units did not exhibit positive linear relationships with speed but instead exhibited nonlinear relationships that peaked at a range of locomotor speeds. Bulk calcium recordings of identified direct and indirect pathway neurons revealed similar speed tuning profiles, indicating that the heterogeneity in response profiles was not due to this genetic distinction. We conclude that continuous encoding of speed is a central component of movement encoding in the striatum.SIGNIFICANCE STATEMENT The striatum is a structure that is linked to volitional movements and is a primary site of pathology in movement disorders. It remains unclear how striatal neurons encode motor parameters and use them to facilitate movement. Here, we evaluated two models for this: a "discrete encoding model" in which striatal neurons facilitate movements with brief burst of activity near the start and end of movements, and a "continuous encoding model," in which striatal neurons encode the sensory or motor state of the animal with continuous changes in firing. We found evidence primarily in support of the continuous encoding model. This may have implications for understanding the striatal control of movement, as well as informing therapeutic approaches for treating movement disorders.

Rodent Activity Detector (RAD), an Open Source Device for Measuring Activity in Rodent Home Cages.

Physical activity is a critical behavioral variable in many research studies and is, therefore, important to quantify. However, existing methods for measuring physical activity have limitations which include high expense, specialized caging or equipment, and high computational overhead. To address these limitations, we present an open-source, cost-effective, device for measuring rodent activity. Our device is battery powered and designed to be placed in vivarium home cages to enable high-throughput, long-term operation with minimal investigator intervention. The primary aim of this study was to assess the feasibility of using passive infrared (PIR) sensors and microcontroller-based dataloggers in a rodent home cages to collect physical activity records. To this end, we developed an open-source PIR based data-logging device called the rodent activity detector (RAD). We publish the design files and code so others can readily build the RAD in their own labs. To demonstrate its utility, we used the RAD to collect physical activity data from 40 individually housed mice for up to 10 weeks. This dataset demonstrates the ability of the RAD to (1) operate in a high-throughput installation, (2) detect high-fat diet (HFD)-induced changes in physical activity, and (3) quantify circadian rhythms in individual animals. We further validated the data output of the RAD with simultaneous video tracking of mice in multiple caging configurations, to determine the features of physical activity that it detects. The RAD is easy to build, economical, and fits in vivarium caging. The scalability of such devices will enable high-throughput studies of physical activity in research studies.