The importance of circadian rhythms for the survival of the individual is unquestionable. These biological rhythms adjust to the daylight cycle and modulate host behavior to optimize survival by adjusting activities to the appropriate time of day. These changes have been found in the sleep cycle, feeding, nerve transmission and hormone secretion patterns, all of which change with day length or photoperiod.
Study: Seasonal changes in day length induce multisynaptic neurotransmitter change to regulate hypothalamic network activity and behavior. Image credit: glass/Shutterstock
A recent paper examined the difference in neuronal communication in the hypothalamic network that regulates physiological function in response to photoperiod. Researchers discovered a new mechanism for adapting to seasonal changes in day length, which could help develop new treatments for seasonal affective disorder (SAD) and other conditions related to seasonal changes in photoperiod.
Introduction
SAD is a mood disorder that causes depressive symptoms that emerge in the winter in people living in the northern hemisphere. Interestingly, exposure to bright light at dawn mitigates symptoms within a few days. This also works with major depressive disorder, bipolar disorder and, to a lesser extent, neurodegenerative diseases such as Parkinson’s or Alzheimer’s disease.
The mammalian brain senses light via intrinsically photosensitive retinal ganglion cells (ipRGCs), which project to the suprachiasmatic nucleus (SCN) of the hypothalamus. This is the pacemaker or master clock of the circadian system. It sets the body to the outer light-dark cycle by coordinating the other parts of the brain with this cycle as well.
Previous research established that seasonal changes in light exposure change the number of AVP neurons in the SCN, neurotransmitter-containing neurons in a region called the paraventricular nucleus (PVN), and a parallel relationship between the two. The PVN is not directly connected to the retina, but receives numerous projections from the SCN.
The SCN contains about 20,000 neurons. The ventral part of the SCN to which ipRGCs project via glutamate-expressing terminals is called the retinohypothalamic tract (RHT). Receptor neurons express vasoactive intestinal peptides (VIPs). Others, in the dorsal SCN, express arginine vasopressin (AVP).
Regardless, most SCN neurons secrete (NT) γ-aminobutyric acid (GABA), an inhibitory neurotransmitter. This acts with GABA to link the different parts of the SCN. This function is intimately connected to neuromedin S (NMS), a neuropeptide found only in the SCN and secreted by 40% of neurons in the SCN, including almost all of those that secrete VIP and AVP. NMS is key to the circadian regulation of body processes.
The coordinated activity of the SCN allows the brain to change its regulatory activity with photoperiod, acting on brain networks and individual neurons. This involves neuronal plasticity through changes in the phases of daily electrical rhythms, as well as altered expression of clock genes in this region.
In animals, altered day length induces plasticity in neurotransmitters, switching between somatostatin and dopamine in the PVN, for example, with corresponding changes in the stress response.
In humans, photoperiod alterations are also related to changes in the number of dopaminergic neurons. The question addressed in this study was whether seasonal changes in light exposure that affected neurotransmitter profiles in the SCN would also cause PVN neurotransmitter plasticity, mediating central regulation of physiological processes and behavioral responses.
What did the study show?
The current study, available online in Science Advances, was conducted in mice.
The results indicate that with a shortened photoperiod, VIP-expressing SCN neurons decrease in number, while NMS neurons that project to PVN dopaminergic neurons increase in parallel.
The researchers observed that with short-day exposure, NMS-negative neurons switched to NMS-positive expression without adding new SCN neurons.
It also changed the co-expression ratio of VIP and NMS, supporting the emergence of a neurotransmitter switch. A similar phenomenon was observed with a subset of non-VIP neurons, which acquired the VIP phenotype when exposed to long days. In addition, SCN-NMS neurons formed a greater number of synapses on PVN dopaminergic neurons under short day length.
With short-day exposure, alterations in the signals of NMS neurons led to a corresponding activation of dopamine-expressing PVN neurons. Conversely, they inhibited corticotropin-releasing hormone (CRH)-expressing PVN neurons.
That is, PVN dopaminergic neurons synchronize to the winter short-day photoperiod through increasing the number of stimuli from an expanded population of NMS neurons in the SCN. PVN neurons appear to achieve this through changes in calcium ion signaling.
Second, they found that NMS neurons are key to the regulation of photoperiodicity-induced physiology by the hypothalamus. According to previous studies, locomotor activity follows a circadian pattern regulated by a SCN-PVN network. The NMS neurons of the former are involved in the regulation of these rhythms through their synaptic connections with other nerve cells.
When the photoperiod is consistently short, chronic inhibition of NMS neurons results in a corresponding reduction in dopamine-expressing neurons in the PVN, a reprogramming of activity within these PVN neurons that results in the observed change in calcium signaling and the neurotransmitter switch. This is associated with a delay in the onset of motor activity. Overall activity remained the same, as did total circadian period.
When mice were exposed to chronic chemogenetic stimulation of NMS neurons with 12-hour light exposure (long photoperiodicity), they began to move on their exercise wheels later in the day. That is, their daily locomotor rhythm showed a delayed onset.
Locomotor amplitude also decreased, along with the appearance of more dopaminergic neurons in the PVN. This was not observed with chronic stimulation of VIP neurons at night.
Thus, stimulation of NMS neurons simulates the effects of a short photoperiod, but the latter those of long-day exposures, with a reduced number of NMS neurons.
What are the implications?
The results of this paper show a clear response of the SCN-PVN network to photoperiodicity, where it induces neuronal plasticity in the PVN, altering its functions and changing the onset time of locomotor rhythms via NMS neurons in the SCN . Neurotransmitter switching in the SCN “occurs by recruiting resident neurons to a fate they would not normally have assumed.”
Some of the newly NMS-expressing neurons come from changing VIP cells and the rest from other cells. SCN memory for photoperiod may be mediated in part by this neurotransmitter switch.
This corroborates and extends the findings of previous animal studies. Researchers have previously shown that VIP mediates synaptic connectivity between neurons in the SCN to produce a reorganized pathway in response to long exposure. This neurotransmitter has been shown to be important for synchronizing the network in this scenario.
The current study reveals that VIP and NMS neurons change in number with photoperiod in response to changes in gene expression. Chemogenetic activation of NMS neurons shows that activation/inhibition of this pathway is sufficient to alter dopaminergic activity in the PVN while keeping the total number of NMS neurons intact. This neurotransmitter switch leads to reorganization of the SCN-PVN circuit, affecting locomotor activity.
The molecular adaptations revealed in the SCN-PVN network may prove useful for the development of new targets and therapeutic approaches to treat seasonal and non-seasonal depression and other cognitive impairments induced by altered light-dark cycles.