Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass, along with adipose tissue wasting, systemic inflammation and other metabolic abnormalities ...leading to functional impairment. Cancer cachexia has long been recognized as a direct cause of complications in cancer patients, reducing quality of life and worsening disease outcomes. Some related conditions, like sarcopenia (age‐related muscle wasting), anorexia (appetite loss) and asthenia (reduced muscular strength and fatigue), share some key features with cancer cachexia, such as weakness and systemic inflammation. Understanding the interplay and the differences between these conditions is critical to advance basic and translational research in this field, improving the accuracy of diagnosis and contributing to finally achieve effective therapies for affected patients.
The execution and learning of diverse movements involve neuronal networks distributed throughout the nervous system. The brainstem and basal ganglia are key for processing motor information. Both ...harbour functionally specialized populations stratified on the basis of axonal projections, synaptic inputs and gene expression, revealing a correspondence between circuit anatomy and function at a high level of granularity. Neuronal populations within both structures form multistep processing chains dedicated to the execution of specific movements; however, the connectivity and communication between these two structures is only just beginning to be revealed. The brainstem and basal ganglia are also embedded into wider networks and into systems-level loops. Important networking components include broadcasting neurons in the cortex, cerebellar output neurons and midbrain dopaminergic neurons. Action-specific circuits can be enhanced, vetoed, work in synergy or competition with others, or undergo plasticity to allow adaptive behaviour. We propose that this highly specific organization of circuits in the motor system is a core ingredient for supporting behavioural specificity, and at the same time for providing an adequate substrate for behavioural flexibility.
Shifting between goal-directed and habitual actions allows for efficient and flexible decision making. Here we demonstrate a novel, within-subject instrumental lever-pressing paradigm, in which mice ...shift between goal-directed and habitual actions. We identify a role for orbitofrontal cortex (OFC) in actions following outcome revaluation, and confirm that dorsal medial (DMS) and lateral striatum (DLS) mediate different action strategies. Simultaneous in vivo recordings of OFC, DMS and DLS neuronal ensembles during shifting reveal that the same neurons display different activities depending on whether presses are goal-directed or habitual, with DMS and OFC becoming more and DLS less engaged during goal-directed actions. Importantly, the magnitude of neural activity changes in OFC following changes in outcome value positively correlates with the level of goal-directed behavior. Chemogenetic inhibition of OFC disrupts goal-directed actions, whereas optogenetic activation of OFC specifically increases goal-directed pressing. These results also reveal a role for OFC in action revaluation, which has implications for understanding compulsive behavior.
Chunking allows the brain to efficiently organize memories and actions. Although basal ganglia circuits have been implicated in action chunking, little is known about how individual elements are ...concatenated into a behavioral sequence at the neural level. Using a task in which mice learned rapid action sequences, we uncovered neuronal activity encoding entire sequences as single actions in basal ganglia circuits. In addition to neurons with activity related to the start/stop activity signaling sequence parsing, we found neurons displaying inhibited or sustained activity throughout the execution of an entire sequence. This sustained activity covaried with the rate of execution of individual sequence elements, consistent with motor concatenation. Direct and indirect pathways of basal ganglia were concomitantly active during sequence initiation, but behaved differently during sequence performance, revealing a more complex functional organization of these circuits than previously postulated. These results have important implications for understanding the functional organization of basal ganglia during the learning and execution of action sequences.
Deciding what to do and when to move is vital to our survival. Clinical and fundamental studies have identified basal ganglia circuits as critical for this process. The main input nucleus of the ...basal ganglia, the striatum, receives inputs from frontal, sensory, and motor cortices and interconnected thalamic areas that provide information about potential goals, context, and actions and directly or indirectly modulates basal ganglia outputs. The striatum also receives dopaminergic inputs that can signal reward prediction errors and also behavioral transitions and movement initiation. Here we review studies and models of how direct and indirect pathways can modulate basal ganglia outputs to facilitate movement initiation, and we discuss the role of cortical and dopaminergic inputs to the striatum in determining what to do and if and when to do it. Complex but exciting scenarios emerge that shed new light on how basal ganglia circuits modulate self-paced movement initiation.
The performance of an action relies on the initiation and execution of appropriate movement sequences. Two basal ganglia pathways have been classically hypothesized to regulate this process via ...opposing roles in movement facilitation and suppression. By using a series of state-dependent optogenetic manipulations, we dissected the contributions of each pathway and found that both the direct striatonigral pathway and the indirect striatopallidal pathway are necessary for smooth initiation and the execution of learned action sequences. Optogenetic inhibition or stimulation of each pathway before sequence initiation increased the latency for initiation: manipulations of the striatonigral pathway activity slowed action initiation, and those of the striatopallidal pathway aborted action initiation. The inhibition of each pathway after initiation also impaired ongoing execution. Furthermore, the subtle activation of striatonigral neurons sustained the performance of learned sequences, while striatopallidal manipulations aborted ongoing performance. These results suggest a supportive versus permissive model, where patterns of coordinated activity, rather than the relative amount of activity in these pathways, regulate movement initiation and execution.
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•Both basal ganglia pathways are required for action sequence initiation and performance•Striatonigral manipulations slowed, but striatopallidal manipulations aborted, initiation•Striatonigral, but not striatopallidal, pathway activation prolonged action sequences•Inhibition or overactivation of the striatopallidal pathway aborted action sequences
The direct and the indirect basal ganglia pathway regulate movements by acting in complementary supportive and permissive manners, rather than by having opposing hyperkinetic and akinetic effects.
Human papillomavirus (HPV) is the most common sexually transmitted infectious agent worldwide, being also responsible for 5% of all human cancers. The integration and hypermethylation mechanisms of ...the HPV viral genome promote the unbalanced expression of the E6, E7 and E5 oncoproteins, which are crucial factors for the carcinogenic cascade in HPV-induced cancers. This review highlights the action of E6, E7 and E5 over key regulatory targets, promoting all known hallmarks of cancer. Both well-characterized and novel targets of these HPV oncoproteins are described, detailing their mechanisms of action. Finally, this review approaches the possibility of targeting E6, E7 and E5 for therapeutic applications in the context of cancer.
•HPV is the main etiological factor of 5% of all human cancers.•E6, E7 and E5 oncoproteins are the main drivers of HPV carcinogenesis.•HPV oncoproteins are implicated in all hallmarks of cancer.•Targeting E6, E7 and E5 is a future promising goal for disease treatments.
Deciding when and whether to move is critical for survival. Loss of dopamine neurons (DANs) of the substantia nigra pars compacta (SNc) in patients with Parkinson's disease causes deficits in ...movement initiation and slowness of movement. The role of DANs in self-paced movement has mostly been attributed to their tonic activity, whereas phasic changes in DAN activity have been linked to reward prediction. This model has recently been challenged by studies showing transient changes in DAN activity before or during self-paced movement initiation. Nevertheless, the necessity of this activity for spontaneous movement initiation has not been demonstrated, nor has its relation to initiation versus ongoing movement been described. Here we show that a large proportion of SNc DANs, which did not overlap with reward-responsive DANs, transiently increased their activity before self-paced movement initiation in mice. This activity was not action-specific, and was related to the vigour of future movements. Inhibition of DANs when mice were immobile reduced the probability and vigour of future movements. Conversely, brief activation of DANs when mice were immobile increased the probability and vigour of future movements. Manipulations of dopamine activity after movement initiation did not affect ongoing movements. Similar findings were observed for the initiation and execution of learned action sequences. These findings causally implicate DAN activity before movement initiation in the probability and vigour of future movements.
Dedicated neuronal circuits mediate execution, choice, and coordination of body action
Movement is the most common final output of nervous system activity and is essential for survival. But what ...makes this seemingly trivial statement so scientifically challenging? Neurons that contribute to when and how our body moves are distributed throughout the nervous system. Thus, even a simple movement such as arm flexion requires the coordinated activation of many different neuronal populations across multiple brain regions. A key question is how the nervous system produces diverse and precise actions aligned with the organisms' behavioral needs. These processes are affected in diseases such as Parkinson's or Huntington's, in which aberrant motor behavior dominates. Recent studies are transformative in how we think about the control of movement. A common denominator of these studies is that brain regions that contribute to motor behavior can no longer be considered as interacting boxes. Instead, deep circuit-level insight based on specific neuronal populations emerges as being critical to revealing motor system organization and understanding its function. It is likely that insights at this level can also help to design more specific and direct interventions for diseases of the motor system and neuroprosthetics applied after injuries.
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