Prefrontal cortex output circuits guide reward seeking through divergent cue encoding

The prefrontal cortex is a critical neuroanatomical hub for controlling motivated behaviours across mammalian species. In addition to intra-cortical connectivity, prefrontal projection neurons innervate subcortical structures that contribute to reward-seeking behaviours, such as the ventral striatum and midline thalamus. While connectivity among these structures contributes to appetitive behaviours, how projection-specific prefrontal neurons encode reward-relevant information to guide reward seeking is unknown. Here we use in vivo two-photon calcium imaging to monitor the activity of dorsomedial prefrontal neurons in mice during an appetitive Pavlovian conditioning task. At the population level, these neurons display diverse activity patterns during the presentation of reward-predictive cues. However, recordings from prefrontal neurons with resolved projection targets reveal that individual corticostriatal neurons show response tuning to reward-predictive cues, such that excitatory cue responses are amplified across learning. By contrast, corticothalamic neurons gradually develop new, primarily inhibitory responses to reward-predictive cues across learning. Furthermore, bidirectional optogenetic manipulation of these neurons reveals that stimulation of corticostriatal neurons promotes conditioned reward-seeking behaviour after learning, while activity in corticothalamic neurons suppresses both the acquisition and expression of conditioned reward seeking. These data show how prefrontal circuitry can dynamically control reward-seeking behaviour through the opposing activities of projection-specific cell populations

Poor functional performance 1 year after ACL reconstruction increases the risk of early osteoarthritis progression

BACKGROUND: Not meeting functional performance criteria increases reinjury risk after ACL reconstruction (ACLR), but the implications for osteoarthritis are not well known. OBJECTIVE: To determine if poor functional performance post-ACLR is associated with risk of worsening early osteoarthritis features, knee symptoms, function and quality of life (QoL). METHODS: Seventy-eight participants (48 men) aged 28±15 years completed a functional performance test battery (three hop tests, one-leg-rise) 1 year post-ACLR. Poor functional performance was defined as <90% limb symmetry index (LSI) on each test. At 1 and 5 years, MRI, Knee injury Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee (IKDC) subjective form were completed. Primary outcomes were: (i) worsening patellofemoral and tibiofemoral MRI-osteoarthritis features (cartilage, bone marrow lesions (BMLs) and meniscus) and (ii) change in KOOS and IKDC scores, between 1 and 5 years. RESULTS: Only 14 (18%) passed (≥90% LSI on all tests) the functional test battery. Poor functional performance on the battery (all four tests <90% LSI) 1 year post-ACLR was associated with 3.66 times (95% CI 1.12 to 12.01) greater risk of worsening patellofemoral BMLs. A triple-crossover hop <90% LSI was associated with 2.09 (95% CI 1.15 to 3.81) times greater risk of worsening patellofemoral cartilage. There was generally no association between functional performance and tibiofemoral MRI-osteoarthritis features, or KOOS/IKDC scores. CONCLUSION: Only one in five participants met common functional performance criteria (≥90% LSI all four tests) 1 year post-ACLR. Poor function on all four tests was associated with a 3.66 times increased risk of worsening patellofemoral BMLs, and generally not associated with decline in self-reported outcomes