Combined Social and Spatial Coding in a Descending Projection from the Prefrontal Cortex.

Social behaviors are crucial to all mammals. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant or how they contribute. We found that PL contains anatomically and molecularly distinct subpopulations that target three downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), amygdala, and ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased the preference for a social target. To determine what information PL-NAc neurons convey, we selectively recorded from them and found that individual neurons were active during social investigation, but only in specific spatial locations. Spatially specific manipulation of these neurons bidirectionally regulated the formation of a social-spatial association. Thus, the unexpected combination of social and spatial information within the PL-NAc may contribute to social behavior by supporting social-spatial learning.

Specialized coding of sensory, motor and cognitive variables in VTA dopamine neurons.

There is increased appreciation that dopamine neurons in the midbrain respond not only to reward1 and reward-predicting cues1,2, but also to other variables such as the distance to reward3, movements4-9 and behavioural choices10,11. An important question is how the responses to these diverse variables are organized across the population of dopamine neurons. Whether individual dopamine neurons multiplex several variables, or whether there are subsets of neurons that are specialized in encoding specific behavioural variables remains unclear. This fundamental question has been difficult to resolve because recordings from large populations of individual dopamine neurons have not been performed in a behavioural task with sufficient complexity to examine these diverse variables simultaneously. Here, to address this gap, we used two-photon calcium imaging through an implanted lens to record the activity of more than 300 dopamine neurons from the ventral tegmental area of the mouse midbrain during a complex decision-making task. As mice navigated in a virtual-reality environment, dopamine neurons encoded an array of sensory, motor and cognitive variables. These responses were functionally clustered, such that subpopulations of neurons transmitted information about a subset of behavioural variables, in addition to encoding reward. These functional clusters were spatially organized, with neighbouring neurons more likely to be part of the same cluster. Together with the topography between dopamine neurons and their projections, this specialization and anatomical organization may aid downstream circuits in correctly interpreting the wide range of signals transmitted by dopamine neurons.

SH003 enhances paclitaxel chemosensitivity in MCF-7/PAX breast cancer cells through inhibition of MDR1 activity.

Paclitaxel is an anti-cancer drug for treating cancer, but paclitaxel resistance is reported in cancer cells. Multidrug resistance (MDR) is related with the epithelial-to-mesenchymal transition (EMT) mechanism, which plays a key role in cancer metastasis. Moreover, EMT mechanism is connected to tamoxifen resistance in breast cancer cells. Consequently, oncologists are interested in finding new MDR1 inhibitors originating from herbal medicines to have less side-effect. Here, we investigated an inhibition effect of SH003 on MDR1 activity in paclitaxel-resistant MCF-7/PAX breast cancer cells. Our results showed that paclitaxel did not inhibit a proliferation in paclitaxel-resistant MCF-7 breast cancer cells. Paclitaxel-resistant MCF-7 cells showed an increase of MDR1 activity, which was confirmed by measuring an amount of accumulated rhodamine 123 in the cells. Also, qRT-PCR and Western blot assays confirmed that paclitaxel-resistant MCF-7 cells exhibited high MDR1 expression level. Furthermore, paclitaxel-resistant MCF-7 cells showed mesenchymal morphology with alterations of EMT markers, and acquired tamoxifen resistance with a decrease of ERα expression. We also found that a combinatorial treatment of SH003 and paclitaxel in paclitaxel-resistant MCF-7 cells caused apoptosis in synergistic manner, which was due to SH003 inhibition of MDR1 expression. Therefore, SH003 could be a potential agent for overcoming MDR in drug-resistant cancer cells.

Acetylcholine demixes heterogeneous dopamine signals for learning and moving.

Midbrain dopamine neurons promote reinforcement learning and movement vigor. A major outstanding question is how dopamine-recipient neurons in the striatum parse these heterogeneous signals. Here we characterized dopamine and acetylcholine release in the dorsomedial striatum (DMS) of rats performing a decision-making task. We found that dopamine acted as a reward prediction error (RPE), modulating behavior and DMS spiking on subsequent trials when coincident with pauses in cholinergic release. In contrast, at task events that elicited coincident bursts of acetylcholine and dopamine, dopamine preceded contralateral movements and predicted movement vigor without inducing plastic changes in DMS firing rates. Our findings provide a circuit-level mechanism by which cholinergic modulation allows the same dopamine signals to be used for either movement or learning depending on instantaneous behavioral context.

Symptom Management and Quality of Life of Breast Cancer Patients Using Acupuncture-Related Therapies and Herbal Medicine: A Scoping Review.

The side effects associated with breast cancer treatments often reduce the patients' quality of life. The effectiveness of acupuncture-related therapies and herbal medicine in managing the side effect is not fully understood. The study included clinical studies published in the 10 years since 2011 and analyzed the effectiveness of the therapies for managing side effects of anticancer treatment. The databases of MEDLINE via PubMed, CENTRAL, EMBASE, OASIS, and NSDL were searched. Thirty studies, including 13 (43.3%) randomized controlled trials (RCTs), 12 (40.0%) before-and-after studies, three (10.0%) case series, one (3.3%) case report, and one (3.3%) non-RCT, were included in this review. The main symptoms identified were aromatase inhibitors-induced arthralgia (AIA), lymphedema, and chemotherapy-induced peripheral neuropathy (CIPN). The types of acupuncture-related therapies applied included manual acupuncture, electro-acupuncture, moxibustion, and electro-moxibustion. In ten studies, eight herbal medications were administered. The Brief Pain Inventory-Short Form (BPI-SF) and Functional Assessment of Cancer Therapy-General (FACT-G) and -Breast (FACT-B) were frequently used to evaluate pain and QoL, respectively. Most studies suggested beneficial effects of acupuncture and herbal medicine on managing pain, daily function, and quality of life in patients going through AIA, CIPN, and/or lymphedema, with mild side effects. The scoping review implies the potential of CAM therapies as promising interventions for managing symptoms which otherwise lack alternative management options, and for improving the quality of life of breast cancer patients.

A Comparison of Dopaminergic and Cholinergic Populations Reveals Unique Contributions of VTA Dopamine Neurons to Short-Term Memory.

We systematically compare the contributions of two dopaminergic and two cholinergic ascending populations to a spatial short-term memory task in rats. In ventral tegmental area dopamine (VTA-DA) and nucleus basalis cholinergic (NB-ChAT) populations, trial-by-trial fluctuations in activity during the delay period relate to performance with an inverted-U, despite the fact that both populations have low activity during that time. Transient manipulations reveal that only VTA-DA neurons, and not the other three populations we examine, contribute causally and selectively to short-term memory. This contribution is most significant during the delay period, when both increases and decreases in VTA-DA activity impair short-term memory. Our results reveal a surprising dissociation between when VTA-DA neurons are most active and when they have the biggest causal contribution to short-term memory, and they also provide support for classic ideas about an inverted-U relationship between neuromodulation and cognition.

Combined Treatment for Lung Metastasis from Hepatocellular Carcinoma: A Case Report.

The survival rate of patients with hepatocellular carcinoma and extrahepatic metastases is very poor. Sorafenib, a targeted chemotherapy agent, has been shown effective for patients with advanced hepatocellular carcinoma (HCC), but it is associated with serious side effects. In addition, although surgery has been regarded as effective for lung metastases from HCC, its use in these patients is limited. Complementary and alternative medicine, including traditional Korean medicine (TKM), is increasingly used in cancer treatment, as it has been found to improve patient quality of life and maintain tumor size. This report describes a 62-year-old Korean woman with lung metastases from HCC. She first underwent surgery (stage IV) and six cycles of adjuvant chemotherapy. She was subsequently treated with sorafenib, but computed tomography showed progressive disease and she experienced the side effects of sorafenib. The patient started treatment with TKM, including pharmacopuncture and herbal medicine, in addition to sorafenib. After 8 weeks of TKM treatment, the size of the metastatic nodules decreased and the sorafenib-associated side effect symptoms improved. These findings suggest that treatment with a combination of TKM and sorafenib may be a promising method for patients with HCC and extrahepatic metastases.