Urodynamics: How the brain controls urination

Coordination between the brainstem and the cortex helps to ensure that urination occurs at an appropriate time.
  1. Anna P Malykhina  Is a corresponding author
  1. University of Colorado Anschutz Medical Campus, United States

The brain and the bladder must communicate to make sure that we only urinate when and where it is appropriate. The process of urination is partly controlled by reflexes and is partly under conscious control (de Groat et al., 2015). As the bladder fills, it sends sensory information to the central nervous system, and when the bladder is full, these signals indicate that it must be emptied soon.

One of the signals going the other way, from the brain to the bladder, is the activation of a part of the brainstem called the PMC, short for pontine micturition center. (The word 'micturition' originally referred to the urge to urinate, but is now often used to describe the process of urination as well). The PMC connects to other centers in the central and peripheral nervous systems to coordinate when urination occurs (Fowler et al., 2008). Many studies have identified and examined the main brain centers involved in the control of urination. However, the connections between these different centers, including when and for how long they become active, remain elusive. It is also unclear how the cortex – the part of the brain responsible for higher thought processes – influences urination.

Now, in eLife, Rita Valentino of the Children’s Hospital of Philadelphia and co-workers – including Anitha Manohar as first author – report how neuronal activity is orchestrated before, during and after urination in rats (Manohar et al., 2017). The researchers evaluated when and where neurons fired in unanesthetized rats as their bladders filled and then emptied by recording neural activity in three regions of the brain that are involved in urination: the PMC, the locus coeruleus, and the medial prefrontal cortex (mPFC; Figure 1). At the same time, they measured both the pressure within the bladder and the frequency of urine output.

The neuroscience of urination.

The medial prefrontal cortex (mPFC) is located behind the forehead at the front of the cortex (green), while the pontine micturition center (PMC) and the locus coeruleus (LC) are located within a part of the brainstem known as the pons (blue). The approximate locations of these regions within the human brain are shaded in the cartoon on the left. These three brain regions both send and receive signals (represented by arrows) to and from each other. Signals from the bladder are relayed via the spinal cord to the LC, and then to other centers in the brain including the PMC. The PMC sends signals to the bladder via the spinal cord. The PMC contains different kinds of neurons. Neurons expressing corticotropin-releasing hormone are labeled Crh+, and are known to be involved in starting urination. Neurons that do not express this hormone are labelled Crh-. The role of these neurons is less clear, but it is possible that they are involved in urine storage. Glut+ and GABA+ indicate neurons that produce glutamate and GABA, respectively. Confirmed connections with unclear effects are marked with a red question mark.

First, Manohar et al. established that all neurons in the PMC show the same firing patterns, characterized by slow background activity and fast bursts during the intervals between urinations. These bursts became rare prior to urination, more prominent during urination, and continued for several seconds after the bladder had been emptied. This timing of neuronal activity suggests that PMC neurons likely play a more complex role in regulating the emptying of the bladder than a simple 'on-off switch'. The bursts of activity in the PMC during the intervals between urinations were also intriguing. It was previously believed that PMC neurons were only active during urination (Betts et al., 1992).

In the seconds before urination, neurons in the locus coeruleus showed ongoing low frequency bursts with stronger theta oscillations (waves of activity that repeat about seven times per second). At the same time, the activity in the locus coeruleus started to more closely match that in the mPFC, though the activity across the mPFC became less synchronized. It is likely that some of these changes help to begin the process of urination by increasing arousal and shifting attention toward the full bladder (Michels et al., 2015).

The relationship between the locus coeruleus (LC) and the PMC is also interesting. These centers are close enough that neuronal activity could be recorded from both regions at the same time. The results showed that LC neurons were activated before PMC neurons, suggesting that the former receives indirect input from the bladder before the stimulus reaches the PMC. This is consistent with earlier observations using fMRI in rats (Tai et al., 2009).

The new findings reported by Manohar et al. raise a few questions. The roles of the brainstem and the cortex in processing information from the bladder, and in coordinating urination, remain unclear. It is also not obvious why PMC neurons show bursts of activity in the intervals between urinations. Recent data suggest that there are different kinds of neurons in the PMC (Figure 1), so it is possible that a specific population of PMC neurons sends signals that help the bladder store urine by releasing different types of neurotransmitters (Hou et al., 2016). Earlier studies also showed that urine storage reflexes are mainly organized in the spinal cord (Drake et al., 2010). However, a group of neurons located in the brainstem might play a role in urine storage too. When activated, these neurons made the external urethral sphincter – the muscle that allows us to choose to start urination – more active (Blok and Holstege, 1999).

We need more data about the pathways through which the locus coeruleus receives information from the bladder before it is transmitted to the PMC. Future experiments should also explore what other regions of the cortex get synchronized or desynchronized during urination. Manohar et al. speculate in these areas, based on the published literature, but further studies are clearly warranted to provide more definitive answers.

References

Article and author information

Author details

  1. Anna P Malykhina

    Anna P Malykhina is in the Division of Urology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, United States

    For correspondence
    anna.malykhina@ucdenver.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9271-3096

Publication history

  1. Version of Record published:

Copyright

© 2017, Malykhina

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 4,340
    views
  • 223
    downloads
  • 12
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Anna P Malykhina
(2017)
Urodynamics: How the brain controls urination
eLife 6:e33219.
https://doi.org/10.7554/eLife.33219
  1. Further reading

Further reading

    1. Neuroscience
    Jing Wang, Min Su ... Hailin Zhang
    Research Article

    The slow-intrinsic-pacemaker dopaminergic (DA) neurons originating in the ventral tegmental area (VTA) are implicated in various mood- and emotion-related disorders, such as anxiety, fear, stress and depression. Abnormal activity of projection-specific VTA DA neurons is the key factor in the development of these disorders. Here, we describe the crucial role of the NALCN and TRPC6, non-selective cation channels in mediating the subthreshold inward depolarizing current and driving the firing of action potentials of VTA DA neurons in physiological conditions. Furthermore, we demonstrate that down-regulation of TRPC6 protein expression in the VTA DA neurons likely contributes to the reduced activity of projection-specific VTA DA neurons in chronic mild unpredictable stress (CMUS) depressive mice. In consistent with these, selective knockdown of TRPC6 channels in the VTA DA neurons conferred mice with depression-like behavior. This current study suggests down-regulation of TRPC6 expression/function is involved in reduced VTA DA neuron firing and chronic stress-induced depression-like behavior of mice.

    1. Neuroscience
    Yongjun Li, Nitin S Chouhan ... Amita Sehgal
    Research Article

    Memory consolidation in Drosophila can be sleep-dependent or sleep-independent, depending on the availability of food. The anterior posterior (ap) alpha′/beta′ (α′/β′) neurons of the mushroom body (MB) are required for sleep-dependent memory consolidation in flies fed after training. These neurons are also involved in the increase of sleep after training, suggesting a coupling of sleep and memory. To better understand the mechanisms underlying sleep and memory consolidation initiation, we analyzed the transcriptome of ap α′/β′ neurons 1 hr after appetitive memory conditioning. A small number of genes, enriched in RNA processing functions, were differentially expressed in flies fed after training relative to trained and starved flies or untrained flies. Knockdown of each of these differentially expressed genes in the ap α′/β′ neurons revealed notable sleep phenotypes for Polr1F and Regnase-1, both of which decrease in expression after conditioning. Knockdown of Polr1F, a regulator of ribosome RNA transcription, in adult flies promotes sleep and increases pre-ribosome RNA expression as well as overall translation, supporting a function for Polr1F downregulation in sleep-dependent memory. Conversely, while constitutive knockdown of Regnase-1, an mRNA decay protein localized to the ribosome, reduces sleep, adult specific knockdown suggests that effects of Regnase-1 on sleep are developmental in nature. We further tested the role of each gene in memory consolidation. Knockdown of Polr1F does not affect memory, which may be expected from its downregulation during memory consolidation. Regnase-1 knockdown in ap α′/β′ neurons impairs all memory, including short-term, implicating Regnase-1 in memory, but leaving open the question of why it is downregulated during sleep-dependent memory. Overall, our findings demonstrate that the expression of RNA processing genes is modulated during sleep-dependent memory and, in the case of Polr1F, this modulation likely contributes to increased sleep.