Homeostatic Design

 

Homeostatic signaling systems must be tailored to the unique properties of each cell type in the brain. In general, homeostatic signaling systems are based on feedback control, an outline of which is diagrammed below. This simple diagram serves to highlight the many questions that remain unanswered despite our recent progress. Ultimately, homeostatic signaling in the brain is likely to involve many interconnected systems such as this, inclusive of not only feedback but also feedforward signaling, and the incorporation of many reversible and irreversible enzymatic reactions. 

 
Homeostatic signaling systems are built upon feedback control. A simplistic signaling system is diagrammed to illustrate how much remains to be learned. Baseline neural function is detected by a sensor. The information from the sensor is compared to the cell set point, which is genomically defined. If the sensor and set point differ, an error signal is produced, integrated over time and fed back into the system as negative feedback. If the error is offset to zero, perfect homeostasis is achieved. We do not know the nature of a true sensor for neural activity, nor do we know how this information is communicated to a genomically defined set point. Therefore, the chemical identity of the error signal and the nature of signal integration remain unknown. Ultimately, cellular and molecular mechanisms must be able to explain the concepts defined in red. Recent work has highlighted the first mechanisms responsible for the bi-directional control of neurotransmission (Gavino et al., 2015).  Additional work has defined mechanisms for the analogue control of presynaptic release (Younger et al., 2013). We have begun to define the intercellular signaling systems that achieve homeostatic communication between cells in the nervous system (Wang et al., 2014; Harris et al., 2015). 

Homeostatic signaling systems are built upon feedback control. A simplistic signaling system is diagrammed to illustrate how much remains to be learned. Baseline neural function is detected by a sensor. The information from the sensor is compared to the cell set point, which is genomically defined. If the sensor and set point differ, an error signal is produced, integrated over time and fed back into the system as negative feedback. If the error is offset to zero, perfect homeostasis is achieved. We do not know the nature of a true sensor for neural activity, nor do we know how this information is communicated to a genomically defined set point. Therefore, the chemical identity of the error signal and the nature of signal integration remain unknown. Ultimately, cellular and molecular mechanisms must be able to explain the concepts defined in red. Recent work has highlighted the first mechanisms responsible for the bi-directional control of neurotransmission (Gavino et al., 2015).  Additional work has defined mechanisms for the analogue control of presynaptic release (Younger et al., 2013). We have begun to define the intercellular signaling systems that achieve homeostatic communication between cells in the nervous system (Wang et al., 2014; Harris et al., 2015). 

 

Homeostatic Plasticity and the Mechanisms of Disease

If homeostatic signaling is impaired, the nervous system will be 

less robust to perturbations including genetic, immunological or 

environmental stress. We are actively exploring the intersection of homeostatic signaling with the genetics of both autism and neurodegenerative disease. We are translating our mechanistic advances to search for novel, disease modifying strategies using mice and other models of disease. The broad clinical expertise at UCSF provides an ideal environment for collaboration. 

Anatomical illustration by Leonardo da Vinci