Organization of the neural switching circuitry underlying reflex micturition

Abstract

The functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain and spinal cord that coordinates the activity of the bladder and urethral outlet. Experimental studies in animals indicate that urine storage is modulated by reflex mechanisms in the spinal cord, whereas voiding is mediated by a spinobulbospinal pathway passing through a coordination centre in the rostral brain stem. Many of the neural circuits controlling micturition exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. This study summarizes the anatomy and physiology of the spinal and supraspinal micturition switching circuitry and describes a computer model of these circuits that mimics the switching functions of the bladder and urethra at the onset of micturition.

Figure 1

Diagram summarizing the reflex pathways that regulate urine storage and voiding in a decerebrate cat. The major focus of the diagram is the organization of spinal circuitry. During the urine storage, distention of the bladder produces a low level of firing in vesical afferent axons in the pelvic nerve, which induces firing in lumbar sympathetic nerves innervating the bladder, bladder ganglia and urethra. This activity is mediated by an intersegmental sacral-lumbar reflex pathway (shown in purple) and produces inhibition of the bladder and contraction of the urethral smooth muscle. Bladder afferent firing also elicits reflex activation of motoneurons innervating the external urethral sphincter (EUS) (shown in red) which induces a EUS contraction (the guarding reflex). The EUS contraction in turn induces firing in EUS afferents (shown in red) which activate inhibitory interneurons in the spinal cord leading to inhibition of bladder preganglionic neurons (PGN) and excitatory interneurons on the ascending and descending limbs of the spinobulbospinal micturition reflex pathway. The bladder-sympathetic and bladder-EUS reflex pathways are very likely multisynaptic but are shown as monosynaptic to simplify the diagram. A third spinal inhibitory mechanism (recurrent inhibition) is mediated by axon collaterals of the PGN which activate inhibitory interneurons (shown in blue) that in turn suppress the firing of excitatory interneurons on the ascending and descending limbs of the spinobulbospinal micturition reflex pathway. Reflex voiding in the decerebrate cat is triggered by bladder distension and afferent firing that activates spinal tract neurons (shown in light blue) in the sacral cord that send information to an excitatory circuit in the periaqueductal gray that in turn activates direct (D) neurons in the pontine micturition centre (PMC) that send excitatory signals back down the spinal cord to bladder PGN and/or excitatory interneurons that synapse with PGN (shown in green). PGN in turn excite peripheral ganglion cells that activate the bladder smooth muscle. Descending activity in the PMC direct neurons also suppresses sympathetic and EUS storage reflexes as well as recurrent inhibition by activating segmental inhibitory interneurons (shown in green). This suppression of spinal inhibitory mechanisms by the PMC enhances voiding efficiency.

Figure 2

Multiunit recordings of reflex activity on a bladder postganglionic nerve in a chloralose anesthetized cat during electrical stimulation (0.8 Hz, 3 v, 0.05 ms duration) of bladder afferent axons in the pelvic nerve. The bladder was distended with saline to a volume below the threshold for inducing micturition. First tracing in the upper right is a recording prior to the onset of stimulation showing that the efferent pathway is inactive. The next tracing shows lack of a response to the first stimulus in a train of stimuli. Further stimulation (lower tracings) induces a gradual increase in the magnitude of a long latency reflex and the eventual emergence of asynchronous firing (last tracing) which indicates the onset of reflex micturition. The diagram on the left shows the spinobulbospinal micturition reflex pathway and the sites of nerve stimulation and recording.

Figure 3

Relationship between single unit activity in the PMC of a decerebrate, unanesthetized cat and reflex contractions of the urinary bladder. Top tracings are blood pressure, middle tracings are ratemeter recordings of unit activity in spikes per second and the bottom tracings are bladder pressure in cm H₂O. Three types of neuronal activity are illustrated: (a) a direct neuron that only fired during a bladder contraction, (b) an inverse neuron that fired between bladder contractions and was inhibited during contractions and (c) an independent neuron that exhibited continuous firing unrelated to bladder contractions. Small increases in blood pressure occurred during bladder contractions. The bladder was distended with saline and maintained under isovolumetric conditions. Horizontal calibration represents 1 min. The three neurons were studied at different times in the same animal.

Figure 4

Diagram illustrating the putative pathways in the periaqueductal gray (PAG) and pontine micturition centre (PMC) that contribute to urine storage and voiding. This circuitry shows the neuronal elements and connections used in our computer model. The right side illustrates the ascending afferent limb of the spinobulbospinal micturition reflex that projects to the PAG, and the left side shows the descending limb that connects the PMC direct neuron to the bladder efferent neuron in the sacral spinal cord. During urine storage as the bladder slowly fills low level of afferent activity activates an excitatory neuron (E) in the PAG which relays information (pathway A) to an inverse neuron (I) in the PMC that in turn provides inhibitory input to the type 1 direct neuron (D) to maintain continence. Bladder afferent input is also received by a second neuron in the PAG (E) that is on the excitatory pathway (pathway B) to the PMC type 1 direct neuron (D) and to a transiently active PMC neuron (T) that fires at the beginning of micturition. However, the PAG excitatory relay neuron (E) is not activated during the early stages of bladder filling because it is inhibited by a tonically active independent neuron (I). The PMC type 1 direct neuron is also inhibited by a tonically active independent neuron (I) located in the PMC. Bladder afferent firing gradually increases during bladder filling which increases feed-forward inhibition of the direct neuron via the PAG–PMC inverse neuron pathway. However, at a critical level of afferent firing, excitatory input to the PAG excitatory relay neuron surpasses the tonic inhibition of the independent neuron and sends signals to the PMC transient neuron which briefly inhibits the inverse neuron reducing inhibitory input to the direct neuron allowing it to overcome tonic inhibition and fire action potentials which activate by an axon collateral (pathway C) a reciprocal inhibitory neuron (R) that suppresses the inverse neuron (I) and further reduces inhibition of the direct neuron (D). The direct neuron then switches into maximal firing mode and sends excitatory input to the spinal efferent pathway to the bladder inducing a large bladder contraction and more afferent firing which further enhances synaptic transmission in the PAG-PMC micturition reflex pathways. The reflex circuitry returns to storage mode as the bladder empties and afferent firing declines. Excitatory neurons are green and inhibitory neurons are red.

Figure 5

Simulated bladder volume (top tracing) and pressure (2nd tracing), bladder afferent firing (3rd tracing) and bladder efferent firing (bottom tracing) during bladder filling (30 mL min⁻¹) and during reflex voiding using our computer model of spinal, PAG and PMC neural pathways and the myocybernetic model of Bastiaanssen et al. 1996 to predict the properties of the bladder, urethra and the afferent firing arising in these structures. Note that as bladder volume increases, bladder pressure remains low, bladder efferent firing is absent, but bladder afferent firing gradually increases eventually reaching a threshold for inducing a micturition reflex as evidenced by an abrupt increase in efferent firing, which induces an increase in bladder pressure and afferent firing and bladder emptying. Bladder efferent firing peaks early during micturition and is maintained until the bladder is empty. The voiding phase is shown on an expanded time scale in the tracings on the right side.