Vasoactive intestinal polypeptide (VIP) expression
and inhibitory circuitry
Masters writing assignment
Supervised by Corette Wierenga
Brenna Fearey 3895300
Neuroscience & Cognition masters
Abstract
The brain is composed of millions of neurons, which connect and influence
each other. This neuronal cooperation leads to coordinated behaviors and cognition.
These connections exist within circuits that are made up of both excitatory and
inhibitory synaptic neurons. The excitatory neurons’ primary neurotransmitter is
glutamate and interneurons are the inhibitory neurons whose neurotransmitter is γaminobutyric acid (GABA). The term interneuron refers to the fact that most of these
neurons have very local axonal connections rather than the longer projecting axons
that are common to principal cells. They make up approximately 20% of all neurons
in the brain and exist across the brain but most research is focused on the cortex and
hippocampus. Excitation and inhibition act in close partnership to direct and shape
neural activity. Without inhibition, excitation can have a “run-away” or “ramp-up”
effect. These states of over-excitation are thought to be symptomatic of epilepsy and
schizophrenia. There are a few different models thought to represent the pattern of
excitation and inhibition in the brain. They included: feedforward, feed-back and
disinhibition. The disinhibitory model is somewhat recently and has been proven
across cortical modalities. The vasoactive intestinal polypeptide (VIP) expressing
interneurons act as disinhibitors of excitatory cells by inhibiting other interneurons.
This allows for attenuating of the signal and more gain control. The report will
elaborate on the VIP protein itself and then within the context of inhibitory circuitry.
Interneurons: a diverse and divisive group
The brain is composed of millions of neurons, which connect and influence
each other in such a way that meaningful information is extracted. This neuronal
cooperation leads to coordinated behaviors and cognition. These connections exist
within circuits that are made up of both excitatory and inhibitory synaptic action.
Principal cells (i.e. pyramidal cells) are the excitatory neurons whose primary
neurotransmitter is glutamate and interneurons are the inhibitory neurons whose
neurotransmitter is γ-aminobutyric acid (GABA)(Freund & Buzsáki, 1996). The term
interneuron refers to the fact that most of these neurons have very local axonal
connections rather than the longer projecting axons that are common to principal
cells. Interneurons make up approximately 20% of all neurons in the brain and exist
across the brain but most research is focused on the cortex and hippocampus due to
their distinct laminar organization(Kepecs & Fishell, 2014; McBain & Fisahn, 2001).
Excitation and inhibition act in close partnership to direct and shape neural activity.
Without inhibition, excitation can have a “run-away” or “ramp-up” effect. These
states of over-excitation are thought to be symptomatic of epilepsy and schizophrenia
amongst other disorders (Zaitsev, 2013).
Aims of this review
The goal of this review is to examine the literature regarding an interneuron
subtype known as the vasoactive intestinal peptide-expressing interneuron (VIP).
After a general description of the peptide and it’s known functions, the rest of the
review will focus on it’s role in inhibition, specifically as an interneuron expressing
the peptide. Next, there will be a discussion on the possibility of a conserved
disinhibitory circuit in the brain and whether it is important to examine how these
circuits are mediated by neuromodulators. Finally, potential future studies based on
past research will be discussed.
Inhibition models
The fundamental balance between excitation and inhibition is controlled by
interneurons inhibiting excitatory neurons and excitatory neurons exciting
interneurons but there are two traditional models that elaborate on the specific
connectivity. The first model, feedback inhibition, is based on the extensive
innervation of interneurons onto principal cells; they not only respond in proportion to
their inputs but also influence the incoming input via inhibition(Isaacson & Scanziani,
2011). This model typically occurs when the excitatory input is local. Feed-forward
inhibition occurs when the excitatory input originates from long-range axons that
innervate both excitatory and inhibitory cells at the destination. Inhibition is
guaranteed in this circuit as the long-range afferents synapse more strongly onto
interneurons than pyramidal neurons. This guarantees some level of inhibition
regardless of the strength of the input (Isaacson & Scanziani, 2011; Pfeffer, Xue, He,
Huang, & Scanziani, 2013) (See figure 1). Recently a third inhibition model has
made headlines. In this disinhibition model, a third player (the VIP cells) acts to
inhibit other interneurons and thus releases the “brakes” on excitatory neurons (Lewis,
2013; Pfeffer, 2014; Wilson & Glickfeld, 2014) (figure 1). This model assumes that
both interneurons and principal cells are in a constant balance of low inhibition and
excitation that shifts when long-range excitation onto disinhibitory interneurons
occurs. The challenge in examining these different models is a body of literature that
is difficult to navigate due to lack of agreement in defining interneuron classes and
even what an interneuron is.
Feedback Inhibition
Feed-forward Inhibition
Disinhibition
Figure 1
Schematic representations of the three inhibition models: Feedback, feed-forward and
disinhibition. Excitatory input originates from long-range axons in feed-forward and
disinhibitory circuits. Red circles are interneurons and blue triangles are pyramidal cells.
Closed circles represent excitatory synapses and open circles represent inhibitory synapses.
Interneuron classes
Since the discovery of interneurons, it has been repeatedly shown that there is
no singular type but rather a myriad of subtypes, which have proven extremely
difficult to classify (Ascoli & Alonso-Nanclares, 2008; DeFelipe et al., 2013). The
challenge in classifying these interneurons is due to their numerous morphologies,
developmental origins, gene expression, connectivity patterns and function. In
addition to the multitude of parameters, they commonly overlap between categories.
For example, a cell may have a basket-like morphology, express parvalbumin (PV)
and have axo-axonic connectivity. Another cell might share the same morphology
and connectivity but express a different genetic marker, like somatostatin (SST).
Prior to the availability of techniques to label a certain cell type, experiments had to
conduct electrophysiological recordings based on morphology or spiking features and
later identify the cell type by immunochemistry(Lanciego & Wouterlood, 2011). The
nature of this work is tedious with a slow output. With the availability of technology
to label certain subtypes of interneurons based on a certain gene, these problems have
begun to diminish (Roux, Stark, Sjulson, & Buzsáki, 2014).
A second issue that arises due to the overlap in categorization is a
disagreement in the literature on which of these categories is most useful or valuable
to their definition. In 2008 and again in 2013, a group of interneuron experts gathered
in an attempt to define interneurons in order to encourage a general nomenclature
across the literature (Ascoli & Alonso-Nanclares, 2008; DeFelipe et al., 2013).
Unfortunately, resistance from other groups desiring other definitions thwarts the
efforts of these nomenclature publications. One group suggests that all interneurons
should be broken into only 3 categories based on the gene expression of parvalbumin
(PV), somatostatin (SST) and the serotonin receptor 5HT3a (5HT3aR). PV cells
make up 40% of all interneurons while SST and 5HT3aR each make up 30% (Rudy,
Fishell, Lee, & Hjerling-Leffler, 2011). While this is a nice breakdown both SST and
5HT3aR neurons coexpress other interneuron markers that can be broken up based on
different functions (Gonchar, Wang, & Burkhalter, 2007). Another group defines
cardinal classes of interneurons based on developmental origins and early genetic
cascades that direct their migration and location in the brain (Kepecs & Fishell, 2014).
In this case, they believe that gene expression markers may reflect regional circuit
influenced maturation rather than interneuron class. Finally, efforts to categorize
interneurons may be limited to research in one brain structure rather than across the
brain. A parallel issue is the definition of interneurons is often limited to those cells
who express GABA and have local axonal connections. Recently, more subtypes are
being identified who have long-range axonal connections and also express GABA and
seem to act in inhibition (Caputi, Melzer, Michael, & Monyer, 2013).
Over the last 50 years, the use of classification was with the aim of extracting
useful information about an interneurons function and purpose. Now, with cell
specific Cre-driver lines and optogenetics, gene expression can be a means to isolate a
group of cells and examine their function within a circuit (Roux et al., 2014). In a
way, the interneuron literature is slowly shifting from a bottom-up perspective, i.e.
examining features to address function, to that of a top-down, i.e. examining function
to determine the valuable features for classification. The future of research on
interneurons is promising due to this shift in perspectives and the availability of these
technologies. The identification of the disinhibitory circuitry controlled by vasoactive
intestinal peptide (VIP) expressing neurons exemplifies the potential of this research
perspective.
Vasoactive intestinal polypeptide (VIP)
The vasoactive intestinal polypeptide (VIP) is a 28-amino acid long peptide.
As the name suggests, it was originally discovered in the gut but has since been found
in the nervous system and is considered a neurotransmitter (Said, 1984). VIP and its
receptors, VPAC1 & 2, are expressed in multiple cell types, including interneurons.
Astrocytes and intravascular tissue only have receptors for VIP (Hajós, Zilles,
Schleicher, & Kálmán, 1988; Larsson et al., 1976; Martin et al., 1992). The
expression pattern shows concentrations primarily in the cortex and hippocampus but
also in thalamic nuclei. VIP neuron morphology is generally characterized with
descending axons with a bipolar, bitufted or multipolar dendritic distribution with a
subset that show a basket-like morphology around pyramidal cell somas (Kawaguchi
& Kubota, 1996). In the cortex most of its dendritic targets occur in layer I, IV and
VI while the cell body is found in layers II/III (Hajós et al., 1988; P. J. Magistretti,
1990). They receive predominately asymmetric synapses, i.e. excitatory, and its
projections are predominately symmetric, i.e. inhibitory synapses, onto both
interneurons and some pyramidal neurons (Csillag, Hajós, Zilles, Schleicher, &
Schröder, 1993; Kawaguchi & Kubota, 1996). Following stimulation of VIP
expressing interneurons, VIP occupies the g-protein coupled adenyl-cyclase receptor
and promotes cAMP formation while concurrently promoting glycogenolysis, a
process involved in breakdown of glycogen for cell metabolism (P. Magistretti, 1998).
Finally, VIP has also been shown to have a direct influence on vasodilation in the
brain with close interactions with pial vessels (Edvinsson et al., 1980). It has been
suggested that the VIP expressing interneuron with its numerous local connections to
pyramidal cells, astrocytes and vasculature and its regulation of cAMP is an ideal
candidate for metabolic homeostasis regulation (P. Magistretti, 1998).
VIP secretion has also been implicated in regulating circadian rhythms. As
previously noted, there is a high concentration of VIP in the thalamic structures. In
the suprachiasmatic nucleus (SCN) VIP modulates GABA-mediated currents. This
modulation is suspected to be involved in synchronizing circadian rhythms as VIP
knockout mice show aberrant circadian rhythms (Aton, Colwell, Harmar, Waschek, &
Herzog, 2005; Itri, Michel, Waschek, & Colwell, 2004; Vosko, Schroeder, Loh, &
Colwell, 2007). Further, at the cellular level, VIP appears to be responsible for
maintaining the clock-cell synchronicity that is crucial to circadian rhythm. There is
also evidence that VIP secretion modulates GABA-mediated synaptic transmission in
the SCN (Itri & Colwell, 2003; Itri et al., 2004; Vosko et al., 2007). Some suggest
that there are two types of VIP release at hand: the first involves synaptic release and
modulation by VIP neurons onto other neurons and the second involves extrasynaptic
release onto other cell types like astrocytes and vascular tissues (P. J. Magistretti,
1990).
In addition to their involvement in metabolism and circadian rhythms, VIP
neurons are involved in the regulation of neuronal circuitry. It has been shown that
exogenous VIP exposure is coupled with an increase in excitatory action (Haas &
Gähwiler, 1992; Sessler, Grady, Waterhouse, & Moises, 1991). It also has been
shown to upregulate the expression of particular neurotrophic factors, BDNF and cfos. Interestingly, VIP does not directly influence this upregulation but rather acts via
NMDA receptors (Pellegri, Magistretti, & Martin, 1998). It was thought that the
concurrent activation of a glutamate afferent onto both the VIP neuron and another
excitatory neuron results in this increase in BDNF and c-fos expression at the
excitatory neuron due to both activation of NMDARs and the release of VIP (see
figure 2). Additionally, pyramidal cells do excite VIP interneurons in the neocortex
(Porter et al., 1998). A difficulty in this explanation is that most synapses of VIP
neurons are predominately onto other interneurons rather than onto pyramidal cells
(Hájos, Acsády, & Freund, 1996). The full circuit would take until the 2010’s to truly
begin to parse.
Figure 2:
Schematic from Magistretti et al. (1998) demonstrating early hypotheses regarding the
regulation of VIP neurons onto excitatory neurons. This model will later be adjusted to
include a secondary interneuron between these two cells.
Up until this point, VIP has been explained in the context of its function as a
peptide. The metabolism, circadian rhythms and vasodilation research typically looks
to VIP as a neuropeptide rather than in the context of inhibition circuitry, i.e. GABA
expression. The nature of available technologies when VIP was first characterized
(1970s-1990s) may have partially caused this divergence in focus of VIP (Köbbert et
al., 2000; Lanciego & Wouterlood, 2011). Due to the variability in interneuron type
and potential function, it was not an easy task to combine its role during inhibition
with other factors like circadian rhythm. With the emergence of technologies that
allow for the inclusion of more variables with stronger controls, these discrepancies
will hopefully be resolved. From this point, the discussion will be on VIP used as a
marker to classify a subset of interneurons.
VIP in the cortex
VIP-expressing interneurons make up a small percentage (10-15%) of all
interneurons in the neocortex and interneurons make up approximately 20% of all
cortical neurons in the brain. Thus VIP interneurons account for approximately 2% of
all cortical neurons (Meinecke & Peters, 1987, Gonchar et al., 2007; Pfeffer et al.,
2013; Pfeffer, 2014). Due to their typical bipolar and radially distributed dendritic
morphology with descending axons, it has been hypothesized that these neurons might
be particularly suited for integrating information across laminae (Bayraktar et al.,
1997).
It has been noted many times in the past that interneurons synapse onto
themselves and onto other interneurons in addition to pyramidal cells (Csillag et al.,
1993; Hajós et al., 1988; Hájos et al., 1996) but it has previously remained unclear
and difficult to ascertain how this impacts the function of a cortical circuit. Three
recent studies, utilizing Cre-driver lines and optogenetic techniques, identified a
recurring pattern of circuitry involving the VIP interneurons acting as disinhibitors of
pyramidal cells in the auditory, somatosensory and visual cortices. As VIP
interneurons synapse with SST interneurons and in part with PV interneurons, these
groups sought to understand the function of interneuron-interneuron synapsing
(Pfeffer et al., 2013). Light-activated excitation of VIP interneurons (via
channelrhodopsin 2) resulted in decreased firing of interneurons (both SST and PV)
and simultaneous increased firing of pyramidal neurons in the auditory cortex (AC)
and medial prefrontal cortex (mPFC) (Pi et al., 2013). The authors then demonstrated
that VIP neurons specifically disinhibit the pyramidal cells responding to tones in the
AC. In a behavioral go-no-go task, the VIP neurons are strongly activated by reward
and punishment, i.e. reinforcement signals. Another study looked in the
somatosensory cortex (barrel cortex) and found that whisking behavior recruited VIP
activity, which preferentially inhibits SST cells (Lee, Kruglikov, Huang, Fishell, &
Rudy, 2013). This recruitment is modulated by the excitatory fibers from the primary
vibrissal motor cortex (vMC) onto VIP neurons. In the visual cortex, the authors
found that the VIP interneurons in layers 2/3 in the visual cortex responded to
locomotion (running) and if locomotion is suppressed so are SST cells (Fu et al.,
2014). This demonstrated another VIP disinhibitory circuit in which the suppression
of SST cells by VIP cells results in an increased V1 pyramidal synaptic response.
This explains early studies linking glutamate release with VIP release and
electrophysiological studies that saw when VIP synaptic responses potentiate; SST
cell synaptic responses are depressed (Kawaguchi & Kubota, 1996; Pellegri et al.,
1998). In an effort to understand how locomotion activates VIP neurons, Fu et al.
(2014) found strong inputs from the cholinergic basal forebrain afferents. This is one
example of a driving input to VIP but it is necessary to explore the potential inputs in
other circuitry as well. It likely that other neuromodulatory inputs act to further
attenuate the gain control that the disinhibition circuit provides.
VIP interneurons frequently co-express other chemical markers, making them
particularly interesting but equally tricky to study. In fact, one study showed that VIP
does not occur in an interneuron without the presence of at least one other common
interneuron markers (Gonchar et al., 2007). This comprehensive coexpression profile
highlights the most common chemical markers: calretinin (CR), somatostatin (SST),
cholecystokinin (CCK), choline acetyltransferase (ChaT) (see figure ##). A subset of
VIP neurons might be integral in cholinergic action; approximately 50-80% colocalize with ChaT, an enzyme involved in synthesis of acetylcholine (ACh)
(Bayraktar et al., 1997; Ouellet & de Villers-Sidani, 2014). The difference between
Gonchar’s (2007) findings and that from Bayraktar (1997) and Ouellet (2014) is
surprising but it may be a consequence of staining techniques, brain area (visual vs.
auditory cortex) and species differences (rat vs. mouse). Future research will require
better investigation of this coexpression pattern as ACh might modulate VIP action.
Interneuron
Total number
marker(s)
of cells/mm3
GABA
51,785
100%
VIP total
12,629
24%
CR+VIP
2,952
23%
CR+SST+VIP
3,210
25%
CR+VIP+CCK
101
0.7%
SST+VIP
4,350
34%
SST+VIP+CCK
207
1.6%
VIP only
0
0%
VIP+ChAT
1,501
2.9%
CCK+VIP
207
1.6%
Percent of cells
Table 1
Data adapted from Gonchar et al (2007). Totals represent the mean number of cells
estimated by optical dissection. Percentages are calculated determined from the total number
of all VIP cells counted expect for the total percentage of VIP cells which is calculated based
on total GABA-positive cells counted.
A number of studies have shown a link between VIP interneurons and ACh
suggesting that ACh might act as a neuromodulator on the circuitry that VIP is
involved in. When the focus on VIP was primarily metabolic and vaso-related, it was
thought that ACh and VIP are linked due to their roles in regulating cortical blood
flow (Cauli & Audinat, 1997; P. J. Magistretti, 1990). More recently it has been
shown that basal forebrain stimulation, and thus ACh release, can depolarize VIP
interneurons, more specifically those expressing the 5HT3aR, while having little
effect on pyramidal cells (Alitto & Dan, 2013; Poorthuis, Enke, & Letzkus, 2014).
Additionally, the VIP disinhibitory circuit in the visual cortex receives afferents from
the basal forebrain that relay information about locomotion and these VIP neurons are
exclusively coexpressing the 5HT3aRs as well (Fu et al., 2014). The basal forebrain
cholinergic afferents project are thought to play a role in attention and enhanced
sensory processing but how this system operates remains relatively unclear in the
literature (Poorthuis et al., 2014). The VIP circuit offers an opportunity to more
closely examine cholinergic serotonergic function.
VIP in the hippocampus
While most research on interneurons has focused on the cerebral cortex, there
are other structures in the brain that are populated by interneurons. For the purpose of
brevity and clarity, this review will only explore the hippocampus, in addition to the
cortex, while touching on a few other related structures. The hippocampus is one of
the most studied structures in the brain due to its ideal laminar structure and cellular
organization allowing for convenient electrophysiological experimentation (Andersen,
Morris, Amaral, Bliss, & O’Keefe, 2006). It has also been implicated in learning and
memory processes and is a structure potentially vulnerable to dysfunction and disease.
Interneurons in the hippocampus suffer the same categorization difficulties as those in
the cortex although it seems that overall they have similar expression profiles and
distribution as in the cortex (DeFelipe et al., 2013; Freund & Buzsáki, 1996).
Synaptic plasticity is the strengthening and weakening at synapses in response to
changes in activity (Ho, Lee, & Martin, 2011; Vogels, Sprekeler, Zenke, Clopath, &
Gerstner, 2011). The hippocampus has been the site of the majority of work in
plasticity (Andersen et al., 2006). As such, many studies examine VIP’s role less in
the context of inhibition and circuitry and more in the context of synaptic plasticity as
a neuromodulator; a distinction that may not be as separate as currently presumed
(Yang et al., 2009; Yang, Lei, Jackson, & Macdonald, 2010).
As in the cortex, it is evident that there are numerous types of interneurons in
the hippocampus and that their coordination and functions are critical to the shaping
of input and output in the hippocampus and they may have different regulatory roles.
In the hippocampus, VIP interneurons are referred to as interneuron-specific
interneurons (IS). These interneurons show preferential innervation onto other
interneurons and express calretinin (CR) and/or VIP. They also show three different
morphologies (Acsády, Arabadzisz, & Freund, 1996). CR-expressing VIP cells have
either a dense axonal network at the stratum oriens or they project to the stratum
radiatum with dendritic material spanning all layers. Another subset of VIP cells
forms a basket-like morphology around pyramidal cells and co-localize with CCK but
not CR (Acsády et al., 1996; Acsady, Görcs, & Freund, 1996; Hájos et al., 1996).
Most VIP interneurons are innervated by the serotonergic afferent from the raphe
nucleus (Papp, Hajos, Acsády, & Freund, 1999), which is interesting as studies in the
cortex have shown co-localization of VIP with 5HT3 receptors (Fu et al., 2014; Rudy
et al., 2011).
Although there have not been breakthrough studies like that by Lee et al.
(2013), Pi et al. (2013), and Fu et al. (2014) in the hippocampus, there is a small
subset of studies suggesting that VIP interneurons enhance excitation in the
hippocampus via pre- and post-synaptic modes and in a disinhibitory manner. The
enhanced excitatory transmission was fully dependent on VIP-dependent release of
GABA (Cuhna-Reis 2004). Similarly, direct application of VIP specifically enhances
NMDA currents in CA1 pyramidal cells (Cuhna-Reis, Yang2009). Considering the
link between enhanced excitation and its unique interneuron-specific contacts, it has
been hypothesized that VIP interneurons’ specialized function is to integrate and
coordinate activity in the hippocampus (Chamberland & Topolnik, 2012).
As VIP appears to act as a neuromodulator of synaptic activity, it is not
surprising that its function has also been examined during long-term plasticity. This
form of plasticity involves a long lasting strengthening or weakening of synapses
(Collingridge, Peineau, Howland, & Wang, 2010). A recent article showed that VIP
interneurons play a role in regulating long-term depression (LTD) in CA1 pyramidal
neurons (Cunha-Reis, Aidil-Carvalho, & Ribeiro, 2014). The authors found that in
the presence of VIP antagonists, there is stronger depression following the LTD
protocol (1 Hz stimulation for 15 mins) than in a naïve situation. This suggests that
VIP endogenously inhibits the strength of LTD in the CA1. This modulation acts
specifically on the VPAC1 VIP receptors, which are present on dendrites in the oriens
and radiatum strata (Joo et al., 2004). The modulation of the LTD strength is also
more affected when VIP is antagonized compared to GABA. This could potentially
be an outcome in which VIP interneurons modulate a circuit and the peptide, itself,
acts on the circuit further. This study is the first to show endogenous regulation of
VIP interneurons on LTD and offers the potential to explore this circuitry further.
The above summated work in VIP and the hippocampus illustrates the
potential for more work and exploration but also the lack of clear knowledge on the
actual role and function of VIP. Although the hippocampal VIP literature shares
similarities with the cortex literature, it’s apparent that VIP is studied more distinctly
as a neuromodulating peptide rather than a specific-type of interneuron. Most articles
note that VIP is expressed by GABAergic neurons and thus suggest that inhibition
might be involved as well but the work remains at the synaptic level rather than
examining the circuitry involved. Recent findings linking VIP and LTD offer an
exciting opportunity to understand how a potential disinhibitory circuit plays a part in
memory formation.
Present and future outlooks
A new model for (dis)inhibition?
With the newly discovered VIP-dependent disinhibition circuit in the cortex, it
stands to question whether this is a specific and unique circuit or if disinhibitory
modulation is a commonality to many circuits in the brain. Presently, it is difficult to
say as these findings are dependent on recent advances in technologies and limitations
in the availability of interneuron subtype-specific Cre-driver lines but some
conclusions can be posed. While VIP interneurons remain particularly unique in their
near sole innervation with other interneurons, other interneurons also demonstrate
interneuron preferences. PV neurons synapse mostly onto pyramidal cells and onto
each other whereas SST neurons synapse onto pyramidal cells, onto each other and
other interneurons (Pfeffer et al., 2013). In addition to the VIP circuit, there is
evidence of disinhibition involving other interneurons. In layer 4 of the cortex, SST
interneurons were shown to disinhibit the pyramidal neurons via inhibition of fastspiking interneurons (most likely PV-cells). The same article also found that
inhibition of layer 2/3 SST cells increased the excitability of pyramidal cells in the
same layer (Xu, Jeong, Tremblay, & Rudy, 2013) (Xu 2013). This could be related to
or the same as the VIP circuit in which VIP cells inhibit SST cells in layer 2/3 (Fu et
al., 2014; Wilson & Glickfeld, 2014).
Layer 1 cells, thought to be made up entirely of interneurons, have been found
to act in multiple disinhibitory circuits. These cells disinhibit layer 2/3 pyramidal
cells via PV cells (Letzkus et al., 2011). In this case, these cells were not subtyped
and could be VIP. Another potential disinhibitor cells could be SST cells as VIP cells
do not prefer PV cells and SST cells synapse more regularly with PV cells (Pfeffer et
al., 2013). Another study found that single bouquet cells in layer 1 disinhibit layer 5
pyramidal cells via inhibition of layer 2/3 interneurons (Jiang, Wang, Lee, Stornetta,
& Zhu, 2013). All these studies suggest that disinhibition is an important and
potentially common function across multiple brain areas: the auditory cortex,
prefrontal cortex, visual cortex, and somatosensory cortex. This evidence suggests
that VIP-regulated circuits are important for integrating input from deep brain areas
like the cholinergic afferents activating VIP neurons in the visual cortex with more
superficial cortical association inputs (Fu et al., 2014; Pfeffer, 2014; Poorthuis et al.,
2014; Wilson & Glickfeld, 2014) (see figure 3).
SST
Long-range inputs
Serotonergic
VIP
Cholinergic
VIP
transmitter
PV
Local inputs
Figure 3
This schematic diagram elaborates on the disinhibitory circuitry described in this report.
VIP interneurons receive input from local and long-range inputs including serotonergic (via
the basal raphe) and cholinergic (via basal forebrain) afferents. When excited VIP
interneurons inhibit predominately SST and some PV interneurons. Finally, this report
proposes that VIP as a neurotransmitter might potential add an extra neuromodulatory action
on local excitatory neurons. Black triangles indicate excitatory synapses and open circles
indicate inhibitory synapses.
Blanket Inhibition
Born from the recent data elaborating on previous models and the newer
disinhibitory circuitry, some suggest that there are multiple canonical inhibitory
circuit motifs (Hangya, Pi, Kvitsiani, Ranade, & Kepecs, 2014). Of these, there is
feedback, feed-forward and disinhibition (see figure 1). Presently, I believe it is of
vital importance to maintain these motifs in order to provide the scaffolding for future
research. The usage of these motifs allows research to form testable hypotheses
aimed at understanding these circuits but in the future it may be that these motifs are
rather different facets to the same gem rather than separate operating entities. A
contrasting perspective, suggests that most inhibition occurs non-specifically and
disinhibitory circuits like that of the VIP interneurons act to “release” this inhibition
and reveal pockets of excitation (Fino, Packer, & Yuste, 2013) (see figure 4).
Figure 4
This diagram demonstrates how VIP interneurons act to release pockets of excitatory neurons
from the blanket of inhibition. Green cells are excitatory, blue are SST cells and the orange
cell is a VIP neuron. By synapsing onto an SST cell, the VIP’s disinhibit pyramidal cells.
Adapted from Karnani, Agetsuma & Yuste, 2014.
Combining disinhibition and the inhibition blanket hypothesis might be more
feasible than at first thought. Most interneurons, though predominately PV and SST,
show dense, local innervation (100-200 um) of pyramidal cells (Fino & Yuste, 2011).
The inhibition blanket hypothesis suggests that the interneurons do not have a built-in
guideline to whom they synapse with but that there are local cues shaping their
synapsing and responses within a circuit. It is important to note that blanket
inhibition does not mean that all pyramidal neurons are constantly and consistently
inhibited at the same time. Rather, they are under the control of interneurons with
different temporal specificities. These dynamics can be dictated by their projections,
i.e. dendritic or perisomatic and also by the nature of their synaptic responses (Fino et
al., 2013; Karnani, Agetsuma, & Yuste, 2014). PV cells are fast-spiking and thus
likely are the first inhibitors while SST cells tend to respond only after numerous
spiking inputs and thus likely are involved in continuing inhibition if stimulation is
strong enough (Karnani et al., 2014; McBain & Fisahn, 2001). Blanket inhibition
attempts, in a way, to bring all different circuit motifs together under one umbrellahypothesis as a way to explain the more global function of excitation and inhibition.
This hypothesis inherently requires more research that will likely need to examine the
problem both from the circuit-specific perspective and also the dense nonspecific
inhibition perspective.
Neuromodulation
Neuromodulation is an important actor in shaping circuitry but has been
running parallel to inhibition research rather than hand in hand (Marder, 2012; Wester
& McBain, 2014). Circuitry examines a group of neurons and how they interact with
each other whereas neuromodulation often examines the effect of modulators at the
level of the synapse or at a non-specific cellular level (Marder, 2012). As
technologies improve and allow better labeling in vivo and in vitro, it is more realistic
to combine neuromodulation with inhibition. It is of paramount interest to examine
how the markers used to identify different classes of interneurons might specifically
dictate and influence the role of the interneuron within its own circuitry. These
neuromodulatory factors co-expressed by numerous interneurons likely represent
information associated with behavior state and allow for greater flexibility within
circuits (Wester & McBain, 2014). VIP is a peptide that increases both cAMP
production and glycogenesis in neurons and astrocytes. Somatostatin is a hormone
that among other things inhibits growth hormone release and adenyl cyclase (Schettini
et al., 1989). Both these neuromodulators together make up potentially 40% of all
interneurons in the cortex (see table 1). By acting on the circuits separately or in
strong conjunction with circuitry, they offer further gain control for circuitry (see
figure 3). Recent work from the hippocampus has shown that neuromodulators are
not always slow acting but can also have rapid effects i.e. cholinergic inputs driving
immediate changes in synaptic response in real time (Lovett-Barron et al., 2014;
Poorthuis et al., 2014). Examining the coupling of neuromodulators to inhibition
circuitry might provide information regarding the differences between interneurons
and the behavioral function of the circuit itself.
What’s next?
This is an exciting time for interneuron research. With the advent of specific
cell-targeting techniques via Cre-driver lines and optogenetics, it is possible to isolate
interneuron subtypes and test their function within a circuit. The discovery of a
disinhibitory circuit that appears to be conserved across the sensory modalities is a big
step towards understanding the relevance of the excitation and inhibition balance in
the brain. Further, it is now possible to study the relevance of these circuits in the
context of behavior. One question for these inhibition models is whether they hold
across behaviors or if some behaviors like whisking and auditory discrimination (Lee
et al., 2013; Pi et al., 2013) engage the disinhibition model while other behaviors like
memory recall may engage a different inhibition model. I would argue that it is likely
a combination of both. It may well be that all models coexist and their recruitment
may depend upon the behavior.
As the disinhibitory circuitry controlled by the VIP cells seems to be
conserved across the sensory cortices, this circuit is a good place to begin further
research. VIP cells also exist in the hippocampus so it would be interesting to
examine whether the disinhibition circuit also exists there. Further, the behaviors that
are linked to this circuitry would be of particular interest as the hippocampus is very
well studied and has been linked to learning and memory function. Particularly in the
hippocampus, much of the research into VIP has been associated with synaptic
plasticity so if the conserved VIP circuit is found in the hippocampus as well, it would
be fascinating to examine the role of the behaviors modulating the circuit and how
long-term synaptic plasticity is modified. Behavioral tests have already shown that
VIP plays a role in inhibiting exploration and enhancing water-maze learning (CuhnaReis 2014).
It has recently been shown, using optogenetic techniques, that long-term
potentiation and long-term depression can activate and inactivate a memory (Nabavi
et al., 2014). In this case the authors utilized fear memory circuitry including the
auditory cortex, amygdala and the thalamus. This circuit might be engaging the same
or similar circuitry to that used in the VIP disinhibition circuitry where VIP activation
was modulated by reward (Pi et al., 2013). This circuit might be particularly
interesting, as most work in the cortex has not examined synaptic plasticity function
of VIP. Additionally as VIP interneurons have been shown to modulate the strength
of LTD, a potential function could be gain control of when a memory is inactivated
(Cunha-Reis et al., 2014). Again, this is an opportunity to further examine synaptic
plasticity in the context of interneuron circuits.
As noted previously, neuromodulators might play an important role within the
inhibitory circuitry. In particular, it would be interesting to examine the VIP circuitry
with a focus on both cholinergic and serotonergic afferents as VIP interneurons can
also express ChaT and 5HT3. Those layer 1 cells, which act in the disinhibitory
circuit with layer 2/3 pyramidal cells, respond to cholinergic input and doubly
interesting are also positive for 5HT3aR (Jiang et al., 2013; Larkum, 2013).
Additionally, this disinhibition via cholinergic input is required for a learned
association of shock with tone. There is already evidence of basal forebrain (BF), i.e.
cholinergic, stimulation modulating the excitation and inhibition of VIP, PV and
excitatory neurons (Alitto & Dan, 2013). In this case, they find that weak versus
strong BF stimulation shifts the inhibitory circuit from the control of PV cells to VIP
cells. This is an example in which a behavior, via neuromodulatory afferents, can
drive a shift in the recruitment of a certain inhibitory scheme. Interestingly, in the
hippocampus cholinergic inputs drive SST cells to strongly inhibit pyramidal cells
during learning for tone and shock association (Lovett-Barron et al., 2014; Wester &
McBain, 2014). As VIP cells often innervate SST cells, it would be useful to
investigate how this circuit could potentially exist and modulate learning. These
findings all suggest that both cholinergic and serotonergic modulators act in learned
behaviors (Letzkus et al., 2011; Wester & McBain, 2014).
Conclusions
VIP interneurons have proven to be quite interesting subjects of study in the
context of inhibition and neuromodulation. While other interneurons are undoubtedly
interesting as well, the advent of new technologies allowed for the discovery of a
potentially canonical disinhibitory circuit regulated by VIP cells. The fact that these
cells also have a role in metabolism, vasodilation, a number of co-expression patterns,
and a role in circadian rhythms point out that this is a peptide that can wear many
hats. Although this complicates our ability to understand all of it’s functions, it also
offers a nice model to examine at length. In the near future, hopefully there will be
studies emerging revealing the how the disinhibition circuit responds to different
types of behaviors and consequently different, potentially neuromodulating, inputs. It
will also be important to begin examining the potential existence of these circuits in
other brain areas like the hippocampus but also others such as the amygdala
(Capogna, 2014). The promise of a new era of interneuron research has arrived and
there is much to look forward to regarding the development of new hypotheses and
the likely wedding of some hypotheses together, such as blanket inhibition and
disinhibition.
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