Neuroscience and Biobehavioral Reviews 56 (2015) 315–329

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

jou rnal homepage: www.elsevier.com/locate/neubiorev

Review

Placing the paraventricular nucleus of the thalamus within the brain

circuits that control behavior

∗

Gilbert J. Kirouac

Departments of Oral Biology and Psychiatry, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

a r t i c l e i n f o a b s t r a c t

Article history: This article reviews the anatomical connections of the paraventricular nucleus of the thalamus (PVT)

Received 6 January 2015

and discusses some of the connections by which the PVT could inﬂuence behavior. The PVT receives

Received in revised form 29 July 2015

neurochemically diverse projections from the brainstem and hypothalamus with an especially strong

Accepted 4 August 2015

innervation from peptide producing neurons. Anatomical evidence is also presented which suggests that

Available online 7 August 2015

the PVT relays information from neurons involved in visceral or homeostatic functions. In turn, the PVT

is a major source of projections to the nucleus accumbens, the bed nucleus of the stria terminalis and the

Keywords:

central nucleus of the amygdala as well as the cortical areas associated with these subcortical regions.

Paraventricular nucleus of the thalamus

Motivation The PVT is activated by conditions and cues that produce states of arousal including those with appetitive

Emotions or aversive emotional valences. The paper focuses on the potential contribution of the PVT to circadian

Arousal rhythms, fear, anxiety, food intake and drug-seeking. The information in this paper highlights the poten-

Nucleus accumbens tial importance of the PVT as being a component of the brain circuits that regulate reward and defensive

Prefrontal cortex behavior with the hope of generating more research in this relatively understudied region of the brain.

Amygdala

Bed nucleus of the stria terminalis

license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Drug addiction Fear Anxiety

Food intake

Circadian rhythms

Contents

1. Introduction ...... 316

2. Midline and intralaminar nuclei of the thalamus ...... 316

3. Types of neurons found in the PVT ...... 317

4. Sources of afferents to the PVT ...... 317

4.1. Brainstem ...... 317

4.2. Diencephalon ...... 317

4.3. Telencephalon...... 318

4.4. Dense innervation of the PVT by peptidergic ﬁbers ...... 318

4.5. Summary of afferents and functional considerations ...... 319

5. Areas innervated by the PVT ...... 319

5.1. Nucleus accumbens and the striatum ...... 320

5.2. Extended amygdala ...... 322

5.3. Cortical areas ...... 322

5.4. Other areas ...... 323

5.5. Summary of efferents and functional circuits ...... 323

6. Summary ...... 323

Acknowledgements ...... 324

References ...... 325

∗

Correspondence to: Department of Oral Biology, Faculty of Health Sciences, 780 Bannatyne Avenue, Winnipeg, Manitoba R3E 0W2, Canada.

E-mail address: [email protected]

http://dx.doi.org/10.1016/j.neubiorev.2015.08.005

316 G.J. Kirouac / Neuroscience and Biobehavioral Reviews 56 (2015) 315–329

1. Introduction

There is growing interest in the potential contribution of the

paraventricular nucleus of the thalamus (PVT) in the modulation

of behavior. Much of this attention has been driven by the recog-

nition that the PVT is a major source of input to the nucleus

accumbens (NAc), an area of the ventral striatum known to medi-

ate motivation and reward. Even so, the numbers of studies that

have focused on the other major sources of inputs to the NAc (pre-

frontal cortex, basolateral amygdala, and hippocampal subiculum)

far exceed those on the PVT. This may be due to the belief that

the PVT and other thalamic midline nuclei are involved in gener-

alized arousal (Groenewegen and Berendse, 1994), which is often

considered a nonspeciﬁc determinant of behavior. The discovery

of potent arousal peptides called orexins (hypocretins) and the

subsequent interest in the contribution of arousal mechanisms to

behavior (Boutrel et al., 2010; Mahler et al., 2014; Sakurai, 2014)

have likely contributed to the recent surge of interest in the PVT

(Kelley et al., 2005; Kirouac et al., 2005). The purpose of the present

paper is to review and evaluate what is known about the anatomy

of the PVT and to integrate this information into a functional frame-

work to help guide future studies. The paper focuses on anatomical

studies that have been done in rodents and readers interested in

the anatomical connections of the PVT in primates should refer to

studies done in that species (Hsu and Price, 2007, 2009) while those

interested in a discussion on the differences between rodents and

primates are referred to other reviews (Colavito et al., 2014; Hsu

et al., 2014). The paper deliberately focuses on the more robust

anatomical connections of the PVT since these are most likely to be

involved in mediating observable behavioral changes in the labora-

tory. As a ﬁnal point, generalizations about the pattern of efferent

and afferent connections of the PVT are made with the intent of

providing insights on how the PVT ﬁts within a complex network

of neuronal systems involved in behavior.

2. Midline and intralaminar nuclei of the thalamus

The PVT is a member of the midline and intralaminar group

of thalamic nuclei originally hypothesized to function as a thala-

mocortical arousal system (Edwards and de Olmos, 1976; Royce

et al., 1989; Vertes and Martin, 1988). As shown in Fig. 1, the shape

of the PVT along with its position relative to other midline and

intralaminar nuclei varies across the anterior-posterior extent of

the thalamus. The PVT is the dorsal most member of the midline

group that includes the intermediodorsal and centromedial nuclei

in addition to the PVT (Bentivoglio et al., 1991; Groenewegen and

Berendse, 1994). The midline group shares common features in that

these nuclei receive strong peptidergic innervation (Freedman and

Fig. 1. Drawing of the nuclei and ﬁber bundles found in the dorsal midline tha-

Cassell, 1994b; Kirouac et al., 2005; Lee et al., 2014) and that they lamus at the anterior (−1.32 mm), middle (−2.76 mm), and posterior (−3.48 mm)

innervate the prefrontal cortex and ventromedial striatal regions levels relative to bregma. AM, anteromedial thalamic nucleus; CM, central medial

thalamic nucleus; fr, fasciculus retroﬂexus; Hb, habenular; IMD, intermediodor-

associated with these cortical areas (Groenewegen and Berendse,

sal thalamic nucleus; MD, mediodorsal thalamic nucleus; PC, paracentral thalamic

1994). The anterior aspect of the PVT (aPVT) is bordered later-

nucleus; PT, paratenial thalamic nucleus; PVT, paraventricular thalamic nucleus;

ally by the paratenial nucleus whereas the mid to posterior aspect sm, stria medullaris of the thalamus. The ﬁgure was produced by modifying images

of the PVT (pPVT) is bordered by the mediodorsal nucleus. The from a stereotaxic atlas of the rat brain (Paxinos and Watson, 2009).

rhomboid and reuniens nuclei are also distinctive midline thala-

mic nuclei found ventral to the centromedial nucleus. The earlier

view of the midline and intralaminar nuclei having a general- 1990). As an example of this, the parafascicular nucleus innervates

ized and nonspeciﬁc arousal inﬂuence on the cerebral cortex is the sensorimotor cortex and the lateral regions of the dorsal stria-

no longer supported. This is in part due to anatomical studies tum which together form a circuit that regulates limb movements

showing that individual members of the midline and intralaminar (Alexander et al., 1990; Groenewegen and Berendse, 1994; Van der

nuclei innervate unique and circumscribed regions of the cortex Werf et al., 2002). This type of anatomical arrangement suggests

(Groenewegen and Berendse, 1994; Van der Werf et al., 2002). that individual midline and intralaminar nuclei are part of special-

It is especially important to appreciate that specialized cortical ized corticostriatal and corticolimbic systems. Indeed, investigators

areas and their striatal targets form functional circuits that regulate now emphasize how different members of midline and intralam-

speciﬁc components of movement and behavior (Alexander et al., inar group of nuclei regulate brain mechanisms associated with

G.J. Kirouac / Neuroscience and Biobehavioral Reviews 56 (2015) 315–329 317

speciﬁc functions related to either attention, movement, cognition 1998). The PVT contains a relatively high concentration of ﬁbers

or emotions (for more details of this subject, see Groenewegen and immunoreactive to tyrosine hydroxylase, the enzyme involved in

Berendse, 1994; Kimura et al., 2004; McHafﬁe et al., 2005; Smith the synthesis of DA and norepinephrine, and phenylethanolamine

et al., 2004; Van der Werf et al., 2002; Vertes, 2006). N-methyltransferase (PNMT), the enzyme involved in the synthe-

sis of epinephrine (Otake and Ruggiero, 1995). In addition, the PVT

contains ﬁbers immunoreactive for serotonin (Otake and Ruggiero,

3. Types of neurons found in the PVT

1995). The source of DA ﬁbers in the PVT is from neurons in the

hypothalamus and not the midbrain (Li et al., 2014a; Otake and

The PVT is composed of neurons with cell bodies that range

Ruggiero, 1995). Norepinephrine ﬁbers in the PVT come from the

from 12 to 20 ␮m and aspiny dendrites that extend several hun-

locus ceoruleus, reticular formation and nucleus of the solitary tract

dred micrometers (Richter et al., 2005; Zhang et al., 2009, 2010a).

whereas those containing epinephrine originate from reticular for-

Parvalbumin, a calcium binding protein associated with fast-ﬁring

mation and the nucleus of the solitary tract (Otake and Ruggiero,

interneurons, and the inhibitory amino acid gamma-aminobutyric

1995; Phillipson and Bohn, 1994). Serotonin ﬁbers appear to origi-

acid (GABA) do not appear to be expressed in the medial thalamus

nate mostly from the dorsal raphe nucleus but almost all serotonin

(Bentivoglio et al., 1991; Celio, 1990). Consequently, it is believed

cell groups were shown to project to the PVT (Otake and Ruggiero,

that there are no GABA intereneurons in the PVT (Bentivoglio et al.,

1995). Many of these brainstem projections have also been con-

1991; Christie et al., 1987). In contrast to the lack of parvalbumin,

ﬁrmed using anterograde tracing methods (Bester et al., 1999; Erro

the calcium binding proteins calbindin and calretinin are highly

et al., 1999; Jones and Yang, 1985; Krout and Loewy, 2000b; Ricardo

expressed in PVT neurons (Celio, 1990; Winsky et al., 1992). A

and Koh, 1978; Ruggiero et al., 1998; Vertes et al., 1986).

number of studies have shown that the PVT is composed primar-

The sources of brainstem inputs to the PVT provide potential

ily of projection neurons that use either the excitatory amino acid

cues to the type of neural signal that the PVT may be processing.

glutamate or aspartate as neurotransmitters (Christie et al., 1987;

First, the PVT is innervated by a number of brainstem regions that

Csaki et al., 2000; Frassoni et al., 1997; Myers et al., 2014). How-

are most prominently associated with visceral functions (Otake

ever, a signiﬁcant number of neurons in the midline thalamus

and Ruggiero, 1995; Phillipson and Bohn, 1994). In addition, the

were found to contain neither of these amino acids (Frassoni et al.,

PVT receives afferents from the lateral region of the parabrachial

1997). Other studies report that some projection neurons in the

nucleus and most regions of the periaqueductal gray matter (Krout

PVT are immunoreactive for enkephalin, substance P, neurotensin

and Loewy, 2000a,b). The parabrachial region serves as a relay of

and galanin (Arluison et al., 1994; Melander et al., 1986; Skoﬁtsch

visceral and nociceptive signals to the forebrain (Cechetto, 1987;

and Jacobowitz, 1985). It is not known if these neuropeptides are

Gauriau and Bernard, 2002) while the periaqueductal gray contains

colocalized with excitatory amino acids within the same neurons

key neural circuits for the expression of defensive behaviors and

or whether they are found in a separate population of neurons. The

the modulation of nociception (Canteras et al., 2010; Heinricher

signiﬁcance of the neurochemical diversity in the PVT is unknown

et al., 2009). With the exception of the nucleus of the solitary

but suggests a level of complexity in how the PVT inﬂuences its

tract, these brainstem projections are not unique to the PVT in that

efferent targets.

they also target many of the other midline and intralaminar nuclei

(Krout et al., 2002; Krout and Loewy, 2000a,b). As proposed over

4. Sources of afferents to the PVT

half a century ago, activity in the brainstem may regulate cortical

arousal levels through a thalamic relay from the brainstem to corti-

Anatomical studies have shown that the PVT and other midline

cal areas (Moruzzi and Magoun, 1949). However, the existence of an

and intralaminar nuclei receive projections from a large number

all-important reticulo–thalamo–cortical arousal pathway has been

of brainstem regions. While many papers have emphasized the

largely discredited by studies showing that complete lesions of the

importance of a bottom-up transmission of information, there is

thalamus have no effect on cortical waves across the sleep-wake

also a robust feedback input from the cortex to the PVT (Li and

cycle (Fuller et al., 2011; Vanderwolf and Stewart, 1988). A more

Kirouac, 2012). A notable characteristic of inputs to the PVT com-

likely hypothesis is that the PVT and other midline and intralami-

pared to other members of the midline and intralaminar group is

nar nuclei transmit information related to the content of a waking

that the PVT receives an especially strong input from the hypotha-

state and these nuclei may contribute to an enhanced level of pre-

lamus (Thompson and Swanson, 2003; Van der Werf et al., 2002)

paredness, vigilance or attention if this content requires a response

including a very dense innervation from neuropeptide containing

(Van der Werf et al., 2002).

neurons (Freedman and Cassell, 1994b; Kirouac et al., 2005, 2006;

Lee et al., 2014; Otake, 2005). This section will highlight the regions

4.2. Diencephalon

of the brain that provide a substantial input to the PVT and the neu-

rotransmitters involved in these projections. The section will also

The ventromedial part of the reticular nucleus of the thalamus is

evaluate how the source and the neurochemistry of these inputs

the only thalamic nucleus providing a projection to the PVT (Chen

may provide ideas on the type of inﬂuence the PVT may exert on

and Su, 1990; Cornwall and Phillipson, 1988; Li and Kirouac, 2012).

behavior.

The reticular nucleus plays a critical role in modulating the ﬂow of

information between the thalamus and the cortex (Guillery et al.,

4.1. Brainstem 1998; McAlonan and Brown, 2002; Pinault, 2004) and the ventro-

medial part of the reticular nucleus receives gustatory and visceral

A number of retrograde tracing studies have identiﬁed the sensory information (Hayama et al., 1994; Stehberg et al., 2001).

nucleus of the solitary tract, locus ceoruleus, laterodorsal tegmen- The fact that the PVT receives input from this part of the reticular

tal nucleus, pedunculopontine tegmental nucleus, parabrachial nucleus indicates that the PVT may be involved in functions related

nucleus, periaqueductal gray, raphe nuclei and the deep mes- to gustatory and visceral inputs. This is in line with the view that

encephalic nucleus of the brainstem as providing a signiﬁcant both the PVT and the ventromedial aspect of the reticular nucleus

input to the PVT (Chen and Su, 1990; Cornwall and Phillipson, receive input from gustatory and visceral neurons in the insular

1988; Kirouac et al., 2006; Krout et al., 2002; Krout and Loewy, cortex and the parabrachial nucleus (Hayama et al., 1994; Krout

2000a,b; Li and Kirouac, 2012; Otake et al., 1994; Otake and and Loewy, 2000a; Li and Kirouac, 2012; Stehberg et al., 2001).

Ruggiero, 1995; Phillipson and Bohn, 1994; Ruggiero et al., Since the reticular nucleus has been hypothesized to be involved in

318 G.J. Kirouac / Neuroscience and Biobehavioral Reviews 56 (2015) 315–329

attention, it is possible that neurons in the PVT contribute to integrate functionally related viscerolimbic information from the

attentional mechanisms related to gustatory and visceral sensory cortex, hypothalamus and the brainstem in a way that helps to

information. select the appropriate behavioral response to a set of conditions. For

The hypothalamus is an important source of inputs to the PVT example, the posterior insular cortex is a gustatory and visceral sen-

(Chen and Su, 1990; Cornwall and Phillipson, 1988; Li and Kirouac, sory cortical area (Shi and Cassell, 1998) and transmission of taste

2012; Otake et al., 1995). While these inputs come from neurons and viscerosensory-related signals to the pPVT from this area of the

scattered throughout the anterior–posterior extent of the hypotha- cortex in addition to those signals arising from the hypothalamus

lamus, it is clear that some regions of the hypothalamus provide and parabrachial nucleus may help guide the behavioral responses

a more prominent projection to the PVT. Areas most consistently associated with reward and aversive properties of ingested food

identiﬁed as sources of inputs to the PVT include the dorsomedial, (Igelstrom et al., 2010; Yamamoto et al., 1995; Yasoshima et al.,

suprachiasmatic, ventromedial, paraventricular, arcuate, suprachi- 2007). The prelimbic and infralimbic cortical areas are important

asmatic nuclei as well as the preoptic, anterior, zona incerta, and for executive functions including the integration of internal phys-

lateral hypothalamic areas (Chen and Su, 1990; Cornwall and iological states with salient environmental cues to guide behavior

Phillipson, 1988; Li and Kirouac, 2012; Otake et al., 1995). Of these, (Heidbreder and Groenewegen, 2003; Kesner and Churchwell,

the dorsomedial nucleus and the suprachiasmatic nuclei appear to 2011). The PVT may integrate emotional saliency information from

provide the most robust innervation of the PVT (Chen and Su, 1990; the prefrontal cortex with viscerosensory and visceromotor related

Cornwall and Phillipson, 1988; Li and Kirouac, 2012; Novak et al., information from the hypothalamus and brainstem to guide behav-

2000; Peng and Bentivoglio, 2004; Thompson et al., 1996; Watts ior. Similarly, the ventral subiculum has been associated with the

et al., 1987; Zhang et al., 2006b). The fact that the PVT receives modulation of emotions and motivation (Bannerman et al., 2004;

projections from the suprachiasmatic nucleus, the main circadian Fanselow and Dong, 2010; McNaughton, 2006; O’Mara et al., 2009)

pacemaker for the brain (Saper et al., 2005), and the dorsome- and is in position to inﬂuence neurons in the aPVT. Consistent with

dial nucleus, a major modulator of circadian rhythms (Saper et al., the hypothesis that the cortex transmits cue or context relevant

2005), has led to the suggestion that the PVT may contribute in cir- information, neurons in the PVT were reported to be activated

cadian rhythms (Colavito et al., 2014; Kolaj et al., 2014). This idea after rats were exposed to cues signaling sweetened water reward

is supported by reports that neural activity in the PVT is enhanced (Igelstrom et al., 2010) or when they were placed in a context asso-

during the active phase of the day (Kolaj et al., 2012; Novak and ciated with a taste aversion (Yasoshima et al., 2007), drug reward

Nunez, 1998; Peng et al., 1995). However, it does not appear that the (Brown et al., 1992; Dayas et al., 2008; Hamlin et al., 2009; Rhodes

PVT has a strong inﬂuence on all circadian rhythms because rodents et al., 2005) and footshock (Beck and Fibiger, 1995; Yasoshima et al.,

with lesions of the PVT display normal light–dark entrainment of 2007). As such, cortical inputs to the PVT may relay signals related

locomotor activity (Ebling et al., 1992; Nakahara et al., 2004). The to the saliency or some other aspect of emotionally relevant events.

PVT may regulate behaviors related to biological rhythms as sug-

gested by one study showing that rats with lesions of the PVT 4.4. Dense innervation of the PVT by peptidergic ﬁbers

displayed less anticipatory locomotor activity to food (Nakahara

et al., 2004). One possibility is that the inputs from the suprachi- The presence of a robust peptidergic ﬁber innervation is one

asmatic and dorsomedial nuclei are just two of the many inputs of the remarkable anatomical features of the PVT. A large num-

that contribute to the enhanced neuronal activity in the PVT during ber of peptides have been localized in ﬁbers in the PVT including

the active phase of the light cycle. The diversity and heterogeneous enkephalin, dynorphin, substance P, somatostatin, vasopressin,

␣

origin of the projections from the hypothalamus to the PVT also sug- -melanocyte-stimulating hormone, gastrin-releasing peptide,

gest that some of hypothalamic projections transmit information neurotensin, galanin, cholecystokinin, neuropeptide Y, CRF, neu-

related to homeostasis as well as circadian and biological rhythms. ropeptide S, agouti related peptide, orexins (hypocretins), and

cocaine- and amphetamine-related peptide (CART) (Battaglia et al.,

4.3. Telencephalon 1992; Clark et al., 2011; Freedman and Cassell, 1991; Haskell-

Luevano et al., 1999; Hermes et al., 2013; Kirouac et al., 2005,

Areas of the prefrontal cortex that are innervated by the PVT are 2006; Lee et al., 2014; Otake, 2005; Otake and Nakamura, 1995).

also a major source of input to the PVT (Chen and Su, 1990; Hurley Fibers containing these peptides are often concentrated in the dor-

et al., 1991; Li and Kirouac, 2012; Sesack et al., 1989; Shi and Cassell, sal midline thalamic group of nuclei including the PVT (Freedman

1998; Vertes, 2004). These neurons originate in layer 6 of the pre- and Cassell, 1991; Otake, 2005; Otake and Nakamura, 1995). In

limbic, infralimbic, and insular cortical areas (Li and Kirouac, 2012). the case of peptides like orexins and CART, these ﬁbers can be

There appears to be some topographical differences in these projec- used to demarcate the anatomical boundaries of the PVT within

tions with the pPVT being innervated more robustly by the insular the dorsal thalamus (Fig. 2) (Kirouac et al., 2005, 2006). The loca-

and infralimbic cortices than is the aPVT. Another source of corti- tion of the neurons providing some of these peptidergic ﬁbers has

cal inputs to the PVT is the subiculum of the hippocampus (Chen been investigated and these studies reveal that these ﬁbers orig-

and Su, 1990; Cornwall and Phillipson, 1988; Li and Kirouac, 2012) inate from neurons distributed in multiple regions of the brain.

which provides a much more robust input to the aPVT than to the For instance, CRF ﬁbers originate from extended amygdala and

pPVT (Li and Kirouac, 2012). Finally, relatively minor projections to parabrachial nucleus (Otake and Nakamura, 1995) whereas chole-

the PVT originate from the septal area and the BST (Chen and Su, cystokinin ﬁbers originated from the hypothalamic dorsomedial

1990; Cornwall and Phillipson, 1988; Dong et al., 2001; Dong and nucleus and the periaqueductal gray region (Otake, 2005). Simi-

Swanson, 2003, 2006; Li and Kirouac, 2012). larly, CART ﬁbers originate from several areas of the hypothalamus

What are possible implications of cortical inputs to the PVT? It is including the arcuate nucleus, zona incerta, periventricular, and lat-

known that pyramidal neurons in layer 6 are interconnected with eral hypothalamus (Kirouac et al., 2006; Lee et al., 2014). Another

different regions of the cortex in addition to providing feedback important point to consider is that a single neuron can contain and

regulation of thalamic relay neurons (Bannister, 2005). Corticotha- release neuropeptides in combination with fast acting neurotrans-

lamic feedback has been shown to sharpen the receptive ﬁelds of mitters like glutamate or GABA (Salio et al., 2006). For example,

sensory relay neurons of the visual system (Briggs and Usrey, 2008). ﬁbers that release orexins in the PVT most likely release dynor-

The signiﬁcance of corticothalamic excitatory feedback on neurons phin and glutamate at the same synapse (Chou et al., 2001; Rossetti

in the PVT is unknown. One possibility is that neurons in the PVT et al., 1998; Torrealba et al., 2003). A number of peptides have been

G.J. Kirouac / Neuroscience and Biobehavioral Reviews 56 (2015) 315–329 319

Fig. 2. The distribution of immunohistochemically stained ﬁbers for orexin and cocaine- and amphetamine-related transcript (CART) are shown in the dorsal midline

thalamus. The shape of the paraventricular nucleus of the thalamus (PVT) varies throughout its rostrocaudal extent but is well deﬁned at each level by heavy orexin (A)

and CART (B) immunoreactivity. The PVT is easily distinguished from immediately adjacent thalamic nuclei by a dense innervation from neurons containing these two

neuropeptides (see Fig. 1 for nomenclature of nuclei in the dorsal thalamus). Numbers indicate approximate distance from bregma. Scale bar = 100 ␮m.

shown to have robust electrophysiological effects on PVT neurons. et al., 1997), aversive visceral stimulation (Yasoshima et al., 2007),

Orexins, peptides that have garnered a great deal of attention for food deprivation (Timofeeva and Richard, 2001), and stimulation

their role in state-dependent arousal (Giardino and de Lecea, 2014; of pain sensitive cardiac sympathetic ﬁbers (Xu et al., 2013).

Mieda and Sakurai, 2012), have been shown to have strong postsyn- Stress-induced activation of the PVT appears to have functional

aptic excitatory effects on PVT neurons (Bayer et al., 2002; Huang implications since a number of studies have shown that the PVT

et al., 2006; Ishibashi et al., 2005; Kolaj et al., 2007). Vasopressin modulates the neuroendocrine and behavioral responses to chronic

and gastrin-releasing peptide have excitatory effects (Hermes et al., stress (Bhatnagar and Dallman, 1998; Bhatnagar et al., 2000, 2002).

2013; Zhang et al., 2006a) whereas CART has inhibitory effects on For example, habituation of the hypothalamic–pituitary–adrenal

PVT neurons (Yeoh et al., 2014). More research is necessary to get axis (HPA) response in rats exposed to a chronic stressor as well

a better understanding of the conditions that promote the release as the enhanced HPA and defensive burying responses were

of these peptides in the PVT and their effects on behavior. eliminated in rats with lesions of the PVT (Bhatnagar et al., 2002,

2003). In summary, the PVT represents a brain region that is

generally active during states of high arousal and following stress-

4.5. Summary of afferents and functional considerations

ful/aversive conditions. The PVT also becomes active during the

presentation of cues/contexts signaling the availability of rewards

The prefrontal cortical areas including the infralimbic, prelim-

or the presence of potential threats. Regardless of their emotional

bic, and insular cortices are a major source of input to the PVT. The

valence, the cues/contexts would produce some level of arousal

dorsomedial nucleus of the hypothalamus, the periaqueductal gray,

which would be integrated and relayed by PVT neurons. The short-

and the lateral parabrachial nucleus also represent other important

and long-term consequences of activation of the PVT are likely to

sources of input to the PVT. In addition to receiving strong pro-

be complex considering the divergent projections the PVT sends

jections from these areas, the PVT also receives projections from

to the prefrontal cortex, NAc and extended amygdala.

neurons scattered throughout the brainstem and hypothalamus.

These more diffuse projection systems to the PVT express an

impressive amount of neurochemical diversity including ﬁber 5. Areas innervated by the PVT

projections involving all of the monoamines (DA, norepinephrine,

epinephrine, and serotonin) and a long list of neuropeptides. Anterograde tracing studies have provided a detailed picture of

The diversity of inputs from functionally different regions of the the areas of the brain that are innervated by the PVT (Li and Kirouac,

brain along with the multiplicity of neurotransmitters/modulators 2008; Moga et al., 1995; Vertes and Hoover, 2008). Fig. 3 shows an

indicates complexity in how neurons in the PVT are modulated. It example of the density of ﬁber labeling in the forebrain produced by

is also informative that many of the neurons that innervate the PVT an injection of the anterograde tracer biotinylated dextran amine

originate from regions of the brain that have viscerosensory and (BDA) in the PVT (Li and Kirouac, 2008). By far the most intense

visceromotor functions. This is highly suggestive of the possibility labeling was found in subcortical regions involving a continuum

that the PVT integrates signals related to visceral or emotional that extents from the NAc of the ventral striatum to the BST and ven-

states. Indeed, many studies have reported an activation of the tral regions of the caudate-putamen ending in the central nucleus

PVT following exposure of rats to stressful or aversive conditions of the amygdala (CeA). In contrast, projections to the prefrontal cor-

including restraint (Bhatnagar and Dallman, 1998; Cullinan et al., tex and other subcortical areas were much weaker (Li and Kirouac,

1995), sleep deprivation (Semba et al., 2001), tail pinch and 2008). This suggests that the PVT may exert its most profound inﬂu-

footshocks (Baisley et al., 2011; Bubser and Deutch, 1999; Smith ence on brain function and behavior via projections to subcortical

et al., 1997; Yasoshima et al., 2007), exposure to footshock context areas. This section will provide a detailed description of the areas of

(Beck and Fibiger, 1995; Yasoshima et al., 2007), swimming stress the brain receiving a signiﬁcant input from the PVT. This anatomi-

(Cullinan et al., 1995; Zhu et al., 2011), predator scent (Baisley et al., cal information will be integrated within a framework of neurons

2011), ultrasonic vocalizations in the dysphoric range (Beckett and circuits known to modulate behavior.

320 G.J. Kirouac / Neuroscience and Biobehavioral Reviews 56 (2015) 315–329

Fig. 3. The ﬁgure shows the anterograde labeling found in the forebrain following the injection of the tracer biotinylated dextran amine (BDA) in the posterior aspect of the

paraventricular nucleus of the thalamus (PVT). In this case, dense labeling can be seen in a continuum that extended from the shell of the nucleus accumbens (NAc), bed

nucleus of the stria terminalis (BST), interstitial nucleus of the posterior limb of the anterior commissure (IPAC) to the central nucleus of the amygdala (CeA). In contrast,

ﬁber density in the infralimbic cortex (IL) and insular cortex (IC) is relatively weak. ac, anterior commissure; aca, anterior commissure, anterior part; AID, agranular insular

cortex, dorsal; cc, corpus callosum; CeC, central amygdala, capsular; CeL, central amygdala, lateral; CeM, central amygdala, medial; CPu, caudate putamen; DI, dysgranular

insular cortex; GI, granular insular cortex; STLD, bed nucleus of stria terminalis, lateral, dorsal; STLP, bed nucleus of stria terminalis, lateral, posterior; STMA, bed nucleus of

stria terminalis, medial, anterior; VP, ventral pallidum. The ﬁgure was produced by modiﬁcation of images previously published (Li and Kirouac, 2008).

5.1. Nucleus accumbens and the striatum in the NAc project to and exert inﬂuence on motor control systems

in the ventral pallidum, lateral hypothalamus, and the periaque-

The NAc is composed of two subterritories: a core which ductal gray region (Baldo and Kelley, 2007; Groenewegen and

surrounds the anterior commissure, and a shell which extends Russchen, 1984; Jordan, 1998; Nicola, 2007; Robinson and Berridge,

medially and ventrally around the core (Heimer et al., 1997a; 2000; Salamone et al., 2007). Ultrastructural evidence indicates

Zahm, 2000; Zahm and Brog, 1992). A number of retrograde trac- that the PVT makes synaptic contact with the spines and dendritic

ing studies have reported that both the core and the shell of shafts of medium spiny neurons (Ligorio et al., 2009; Meredith

the NAc are innervated by the PVT (Berendse and Groenewegen, and Wouterlood, 1990; Pinto et al., 2003) and not with choliner-

1990; Brog et al., 1993; Bubser and Deutch, 1998, 1999; Freedman gic interneurons (Ligorio et al., 2009). In addition to using GABA

and Cassell, 1994b; Li and Kirouac, 2008; Moga et al., 1995; as a neurotransmitter, medium spiny neurons produce one of two

Otake and Nakamura, 1998; Su and Bentivoglio, 1990; Vertes and opioid peptides (Furuta et al., 2002; Lee et al., 1997; Zhou et al.,

Hoover, 2008). The sources of these ﬁbers are neurons found in the 2003): enkephalins, which have been linked to positive affective

rostrocaudal extent of the PVT (Fig. 4B) (Li and Kirouac, 2008). Fur- states, or dynorphins, which have been linked to negative emo-

thermore, injections of the anterograde tracers Phaseolus vulgaris tional states and relapse to drug seeking (see reviews byKelley

leucoagglutinin (PHA-L) and BDA in the PVT result in very dense et al., 2005; Nestler and Carlezon, 2006; Shippenberg et al., 2001).

ﬁber labeling in both the core and the shell of the NAc (Berendse However, it is not known if the PVT makes synapses preferen-

and Groenewegen, 1990; Li and Kirouac, 2008; Moga et al., 1995; tially on one type of medium spiny neurons. The PVT also appears

Vertes and Hoover, 2008). Some labeling is also observed in the to regulate the release of dopamine, an important neuromodula-

medial and ventral aspects of the caudate-putamen including an tor of excitatory inputs to medium spiny neurons (Ikemoto, 2007;

area referred as the fundus striati or the interstitial nucleus of the Kelley, 1999; Stratford and Kelley, 1999). Indeed, ﬁber terminals

posterior limb of the anterior commissure (IPAC) (Berendse and that originate from neurons in the PVT make close contact with

Groenewegen, 1990; Li and Kirouac, 2008; Moga et al., 1995; Vertes dopamine terminals (Pinto et al., 2003) and electrical stimulation

and Hoover, 2008). of the PVT stimulates the release of dopamine in the NAc (Parsons

The majority (90–95%) of neurons in the NAc and the stria- et al., 2007). The mechanism for this release appears to involve acti-

tum are medium spiny projection neurons that use GABA as a vation of presynaptic ionotropic glutamate receptors on dopamine

fast inhibitory neurotransmitter (Furuta et al., 2002; Zhou et al., ﬁbers (Parsons et al., 2007). Presynaptic release of dopamine occurs

2003) while the remainder are interneurons that use acetylcholine independently from the ﬁring rate of dopamine neurons in the ven-

or GABA as neurotransmitters (Calabresi et al., 2000; Koos and tral tegmental area and is a feature associated with other glutamate

Tepper, 1999; Tepper and Bolam, 2004). Medium spiny neurons inputs to the NAc (Grace, 1991). While the functional signiﬁcation

G.J. Kirouac / Neuroscience and Biobehavioral Reviews 56 (2015) 315–329 321

Fig. 4. Drawing showing the location of cholera toxin B (CTb) retrogradely labeled cells (ﬁlled circles) in the anterior to posterior regions of the paraventricular nucleus of

the thalamus (PVT). The ﬁgure shows orexin ﬁbers in the PVT and the rest of the midline thalamus (A) following injections of CTb in the shell of the nucleus accumbens (B),

lateral bed nucleus of the stria terminalis (C), and central nucleus of the amygdala (D). CM, central medial thalamic nucleus; Hb, habenular; IMD, intermediodorsal thalamic

nucleus; MD, mediodorsal thalamic nucleus; PC, paracentral thalamic nucleus; PT, paratenial thalamic nucleus. The ﬁgure was produced by modiﬁcation of images previously

published (Li and Kirouac, 2008). Scale bar = 500 ␮m.

of presynaptic release of dopamine by the PVT is unknown, it may levels of arousal including by food deprived states or in conditions

be that this release has an arousal effects on behavior by facilitat- involving palatable food.

ing the ﬂow of information through the NAc (Hauber, 2010; Horvitz, There has also been interest in the contribution of the PVT

2000; Salamone and Correa, 2002). to drug seeking (see reviews byHaight and Flagel, 2014; James

It has been recognized for some time that the NAc has a cru- and Dayas, 2013; Martin-Fardon and Boutrel, 2012; Matzeu et al.,

cial role in motivation and goal directed behavior including food 2014). The PVT is activated by a single exposure to addictive drugs

intake and drug addiction (Kelley et al., 2005; Mogenson et al., (ethanol, cocaine, amphetamine, morphine, cannabinoids, nico-

1980; Nicola, 2007; Pennartz et al., 1994). Multiple lines of evi- tine), exposure to cues/context previously paired with addictive

dence support a role for the PVT in food intake. For instance, lesions drugs, and by reinstatement of drug seeking behaviors (Allen et al.,

of the PVT or inactivation of the pPVT with the GABA agonist mus- 2003; Barson et al., 2014; Brown et al., 1992; Dayas et al., 2008;

cimol increased food intake in rats (Bhatnagar and Dallman, 1999; Deutch et al., 1998; Franklin and Druhan, 2000; Garcia et al., 1995;

Stratford and Wirtshafter, 2013). Further evidence points to the Gutstein et al., 1998; James et al., 2011; Perry and McNally, 2013;

possibility that the PVT may be involved in some aspects of food Ren and Sagar, 1992; Rhodes et al., 2005; Ryabinin and Wang, 1998;

reward behavior. Using cFos as a maker of neuronal excitation, Wedzony et al., 2003). The recruitment of the PVT during drug

the PVT was found to be activated following the presentation of seeking appears to be functionally relevant since a number of stud-

cues that predicted delivery of a sucrose solution (Igelstrom et al., ies have reported that inactivation of the PVT interferes with this

2010) or when rats are placed in a context that had been previously behavior. For example, lesions of the PVT prevented the psychomo-

paired with palatable food (Choi et al., 2010). In fact, the PVT may be tor sensitization produced by repeated administrations of cocaine

strongly recruited in situations involving food reward since plac- (Young and Deutch, 1998) and attenuated context-induced rein-

ing rats in a context paired with regular rat chow did not increase statement of alcohol seeking (Hamlin et al., 2009). In other studies,

neural activity in the PVT (Choi et al., 2010). Other evidence shows injections of GABA agonists in the PVT interfered with the expres-

that the PVT is recruited in response to the motivational properties sion of conditioned place preference to cocaine (Browning et al.,

of a food reward and not because of its affective properties (Flagel 2014) while injections of sodium channel blocker tetrodotoxin

et al., 2011). In addition, orexins released in the PVT may serve as attenuated drug-primed reinstatement of bar pressing for cocaine

a neurochemical signal for food reward since contextual cues that (James et al., 2010). The contribution of the neuropeptides orexins

predicted the availability of palatable food were found to activate and CART acting on the PVT to drug seeking has also been exam-

orexin neurons in the hypothalamus as well as orexin 1 receptor ined. Blocking of orexin 2 receptors (OX2R) in the aPVT was found

(OX1R) expressing neurons in the PVT (Choi et al., 2010). Consistent to attenuate consumption of ethanol, an effect that was not present

with this, knockdown of the OX1R in the PVT was reported to atten- following blocking OX2R in the pPVT or OX1R in the aPVT (Barson

uate overconsumption of sweet high-fat pellets in food deprived et al., 2014). Another study reported an increase in cue-induced

rats (Choi et al., 2012). As a whole, experimental evidence indicates expression of cFos in CART neurons that project to the PVT in rats

that the PVT contributes to food intake in situations involving high trained to self-administer ethanol (Dayas et al., 2008). The same

322 G.J. Kirouac / Neuroscience and Biobehavioral Reviews 56 (2015) 315–329

group demonstrated that CART inhibited cocaine-induced hyper- by local injections of the GABA agonist muscimol attenuated fear

excitability of PVT neurons and that injections of CART in the PVT to a conditioned auditory tone when tested 24 h later (Li et al.,

attenuated drug-primed reinstatement of cocaine (James et al., 2014b; Padilla-Coreano et al., 2012). The recruitment of the PVT

2010). It is clear that much more work is needed to decipher the role in fear appears to require the elapse of time (>8 h) which sug-

of the PVT in drug-related behaviors. Studies using cFos indicate gests that the PVT may be involved in the retrieval of consolidated

that neurons in the PVT are recruited by exposure of experimental fear memories (Padilla-Coreano et al., 2012). Multifaceted evidence

animals to addictive drugs and food as well as the conditions that collected using anatomical, electrophysiological, and optogenetic

predicting their availability. An arousal-mediated increase in PVT approaches indicate that a prelimbic-PVT-lateral CeA pathway

activity may serve to “energize” goal seeking by the activation of mediates the retrieval of a fear memory (Do-Monte et al., 2015).

medium spiny neurons involved in the motor responses associated Recent evidence indicates that the PVT is involved in fear learning

with this behavior. Possible mechanisms for this energizing effect and expression through a brain-derived neurotrophic factor (BDNF)

could involve an excitatory effect of PVT afferents on medium spiny projection from the PVT to the CeA which produces a tropomysin-

neurons in the NAc (Ligorio et al., 2009; Meredith and Wouterlood, related kinase B (TrkB) mediated synaptic plasticity in somatostatin

1990; Pinto et al., 2003) and/or a PVT-mediated release of dopamine neurons that store the fear memory (Penzo et al., 2015).

from ﬁber terminals in the NAc (Jones et al., 1989; Parsons et al., Other lines of evidence demonstrate that activation of the pPVT

2007). generates anxiety and other aversive states through the release of

orexins in the pPVT. As discussed earlier, the PVT receives a dense

5.2. Extended amygdala innervation from orexin neurons where this peptide has strong

excitatory effects. A number of studies show that orexin neurons

Anterograde studies have reported the existence of a projection are activated by stressful conditions (Chen et al., 2014a,b; Espana

from the PVT to a region of the basal forebrain that forms a con- et al., 2003; Furlong et al., 2009; Ida et al., 2000; Winsky-Sommerer

tinuum that extends along the anterior commissure (Berendse and et al., 2004; Zhu et al., 2002) and that orexin neurons are involved

Groenewegen, 1990; Li and Kirouac, 2008; Moga et al., 1995; Vertes in the physiological and behavioral responses to stress (Chen et al.,

and Hoover, 2008). This continuum is called the extended amyg- 2014b; Furlong et al., 2009; Johnson et al., 2010; Kayaba et al., 2003;

dala and includes the BST and the centromedial amygdala (Alheid, Zhang et al., 2010b). Since the pPVT projects heavily to areas of

2003; de Olmos et al., 2004; de Olmos and Heimer, 1999; Heimer the extended amygdala linked to negative emotional behaviors, the

et al., 1997b). As part of this projection system, the PVT projects pPVT represents a good candidate for mediating some of the stress-

most heavily to the dorsolateral BST and in the lateral and capsu- induced behavioral responses associated with orexins. In support

lar subnuclei of the CeA (Li and Kirouac, 2008; Vertes and Hoover, of this idea, microinjections of orexin A and orexin B in the pPVT

2008) where these ﬁbers make putative contacts with CRF neurons elicited anxiety in rats (Heydendael et al., 2011; Li et al., 2009,

(Li and Kirouac, 2008). Retrograde tracing experiments indicate 2010a,b) and microinjections of an OX2R antagonist in the pPVT

that these ﬁbers originate from neurons in the rostrocaudal extent attenuated the anxiety produced after exposing rats to relatively

of the PVT with a predominance of ﬁbers originating from neu- intense footshocks (Li et al., 2010b). These results are consistent

rons in the pPVT (Fig. 4C and D) (Li and Kirouac, 2008). Similar with the increase in the levels of prepro-orexin mRNA reported to

to the mechanism proposed for the nucleus accumbens, the PVT occur in rats exposed to moderately intense footshocks (Chen et al.,

may also inﬂuence neurons in the BST and CeA by direct synaptic 2014a,b). The behavioral effects of orexin receptor antagonism in

contact. In support of this idea, electrical stimulation of the PVT the PVT may be dependent of the type of defensive behavior stud-

was found to elicit orthodronic activation of a majority of neurons ied as shown by recent observations that microinjections of a dual

tested in the CeA (Veinante and Freund-Mercier, 1998). The lat- orexin antagonist in the PVT had no effect on the freezing associ-

eral CeA and the dorsolateral BST contain a very dense dopamine ated with contextual fear while decreasing avoidance by the same

ﬁber plexus (Freedman and Cassell, 1994a) and PVT afferents over- rats placed in a social interaction test (Dong et al., 2015). It is also

lap with dopamine dense regions of the extended amygdala in possible that orexins act preferentially on the PVT during situa-

addition to those of the striatum (Parsons et al., 2007). Conse- tions involving vigilant and hyperaroused states. Other evidence

quently, the PVT may also exert inﬂuence indirectly on neurons indicates that orexins released in the PVT may also be involved

in the BST and CeA through presynaptic modulation of dopamine in the retrieval of memories associated with negative emotional

release. In addition, the regions of the extended amygdala that con- states. In this case, blocking of OX2R in the pPVT attenuated the

tain CRF neurons are also rich in other neuropeptides including expression of the conditioned place avoidance produced by mor-

dynorphin, enkephalin, neurotensin, somatostatin (Cassell et al., phine withdrawal without affecting the acquisition of this behavior

1986, 1999; Marchant et al., 2007; Poulin et al., 2009). In the case (Li et al., 2011). While the pathway for orexin-PVT mediated anx-

of dynorphin, this peptide is co-localized with CRF in many neu- iety or avoidance are not known, PVT projections to the extended

rons in the dorsolateral BST (Marchant et al., 2007) and represents amygdala may be involved. As discussed above, the PVT makes close

another neurochemical substance potentially under the inﬂuence synaptic contact with CRF neurons in the extended amygdala that

of the PVT. Consequently, the PVT may exert some of its effects are known for mediating anxiety (Walker et al., 2009). Is support of

on behavior by direct activation of peptide speciﬁc neurons in the this potential mechanism, central administrations of a CRF antago-

extended amygdala or indirectly by stimulating dopamine release nist attenuated the anxiety produced by microinjections of orexins

which could act on subsets of neurons with dopamine receptors. in the PVT (Li et al., 2010b).

The projections between the PVT and the dorsolateral BST and

the capsular/lateral CeA may place the PVT in a strong position to 5.3. Cortical areas

inﬂuence emotions because these regions of the extended amyg-

dala project directly to areas in the hypothalamus and brainstem As mentioned in the introduction, the PVT and other midline and

involved in the regulation of autonomic and motor responses asso- intralaminar nuclei are often characterized as providing a major

ciated with fear and anxiety (Dong et al., 2001; Petrovich and input to the cerebral cortex (for discussion of topographical pro-

Swanson, 1997). Indeed, there is emerging evidence that support jections of individual nuclei, see Groenewegen and Berendse, 1994;

a role for the PVT in the behavioral responses to these emotional Van der Werf et al., 2002). Indeed, the PVT projects to all layers of

states. The ﬁrst evidence for this is provided by studies showing the infralimbic cortex and the ventral portion of the prelimbic cor-

that lesions of the PVT or inactivation of the midline thalamus tex (Berendse and Groenewegen, 1991; Li and Kirouac, 2008; Moga

G.J. Kirouac / Neuroscience and Biobehavioral Reviews 56 (2015) 315–329 323

et al., 1995; Vertes and Hoover, 2008). The infralimbic and prelimbic 1992; Wright and Groenewegen, 1995) while PVT and dysgran-

cortices have been implicated in the regulation of emotional, exec- ular/agranular insular afferents terminate in the dorsolateral BST

utive and memory processes (Heidbreder and Groenewegen, 2003; and the capsular/lateral part of the CeA (McDonald et al., 1999).

Vertes, 2006) and are important for the integration of internal phys- A similar type of arrangement has been described for subiculum

iological states with salient environmental cues to guide behavior and PVT afferents to the NAc (Meredith and Wouterlood, 1990) as

(Euston et al., 2012; Heidbreder and Groenewegen, 2003). In addi- well as the basolateral amygdala and PVT afferents to the NAc and

tion, the PVT innervates the agranular and dysgranular portions of the capsular CeA (Savander et al., 1995; Wright and Groenewegen,

the multisensory insular cortex (Berendse and Groenewegen, 1991; 1996). In addition, there is extensive collateralization of PVT effer-

Li and Kirouac, 2008; Moga et al., 1995; Vertes and Hoover, 2008) ents to its forebrain targets (Bubser and Deutch, 1998; Otake and

which is known to process nociception, visceral, gustatory sensory Nakamura, 1998; Su and Bentivoglio, 1990) including the medial

information (Kobayashi, 2011). The aPVT also innervates the ven- prefrontal cortex and the NAc (Bubser and Deutch, 1998; Otake

tral subiculum, an area of the hippocampus involved in modulating and Nakamura, 1998). This complex anatomical arrangement indi-

both emotional and motivated behaviors (Bannerman et al., 2004; cates that the PVT can inﬂuence infralimbic, prelimbic, and insular

Fanselow and Dong, 2010; O’Mara et al., 2009). This overall pat- cortices at both the cortical and subcortical levels (striatum and

tern of cortical innervation places the PVT in position to inﬂuence a extended amygdala levels). However, based on the density of ﬁber

wide range of processes important for mediating adaptive and goal labeling observed following injections of anterograde tracers in the

directed behavior. However, the importance of the PVT projections PVT (see Fig. 3), it is likely that this inﬂuence is greater at subcortical

to cortex versus its subcortical targets is unknown. than it is at cortical levels.

5.4. Other areas

6. Summary

A number of other areas are innervated by the PVT. Besides

the CeA, which has been described above, various regions of the A summary of the more robust outputs and inputs of the PVT

amygdala have also been reported to receive a projection from the along with their potential inﬂuence on behavior is shown in Fig. 5.

PVT. These include the basomedial, basolateral, medial, and lateral The efferent connections of the PVT are remarkable for a number

nuclei of the amygdala where a variable amount of labeling was of reasons. First, the PVT is uniquely positioned to inﬂuence the

reported by different studies (Berendse and Groenewegen, 1990, infralimbic, prelimbic and anterior insular cortical circuitry at its

1991; Li and Kirouac, 2008; Moga et al., 1995; Vertes and Hoover, cortical and subcortical levels. In a similar manner, the PVT is also

2008). The PVT may exert inﬂuence on behavior through these in an anatomical position to regulate subiculum/basolateral amyg-

projects in addition to those to the CeA, BST and NAc (Cardinal et al., dala projection systems to the NAc and the extended amygdala.

2002). However, the PVT provides a much weaker projection to This places the PVT in a position to inﬂuence the key forebrain

these areas of the amygdala than it does to the CeA (Li and Kirouac, circuits believed to contribute to behavior. The type of inﬂuence

2008). Other areas shown to receive a relatively weak to moder- the PVT has on the ﬂow of information through these circuits

ate projection from the PVT include the suprachiasmatic, arcuate, remains unknown. One possibility is that the convergence of PVT

dorsomedial and ventromedial nuclei of the hypothalamus as well and cortical afferents on the same medium spiny neurons in the

as the lateral hypothalamus and lateral septal area (Li and Kirouac, NAc and extended amygdala could lead to enhanced activity of

2008; Moga and Moore, 1997; Moga et al., 1995; Vertes and Hoover, medium spiny projection neurons in a way that promotes goal

2008). seeking behavior. Similarly, the convergence of basolateral amyg-

dalar and other cortical inputs on medium spiny neurons in the

5.5. Summary of efferents and functional circuits extended amygdala may promote the expression of emotions like

fear and anxiety. It is also possible that PVT and cortical affer-

It is clear that the projection to the NAc is by far the most impres- ents synapse on a different population of medium spiny neurons

sive of all projections made by the PVT (Li and Kirouac, 2008). with a unique projection pattern or neurochemical identity (e.g.,

Another dense projection system exists between the pPVT and the enkephalin vs dynorphin). In this case, preferential activation of

dorsolateral BST and the capsular/lateral CeA. Interestingly, the one type of medium spiny neurons by the PVT could potentially

regions that receive a very dense projection from the PVT share promote either reward (enkephalin) or defensive behaviors (dynor-

common features. First, the dorsolateral BST and capsular/lateral phin/CRF).

CeA are composed mostly of GABA neurons with a similar morphol- A large number of brain regions provide afferents to the PVT,

ogy as the medium spiny neurons found in the NAc and the striatum many of which originate from neurons located diffusively through-

(Sun and Cassell, 1993). Second, like in the striatum, medium out the hypothalamus and brainstem. These projection systems

spiny neurons of the dorsolateral BST and capsular/lateral CeA use are neurochemically diverse with many of these ﬁbers contain-

GABA as a fast neurotransmitter but also co-localize dynorphin, ing monoamines and neuropeptides. It is also revealing that many

enkephalin and/or other neuropeptides (Marchant et al., 2007; of the neurons that innervate the PVT originate from regions of

Poulin et al., 2009). Third, the parts of the CeA, BST, NAc inner- the brain that have visceral functions. This suggests that the PVT

vated by the PVT are very densely innervated by dopamine ﬁbers may integrate signals related to visceral or emotional states. As dis-

(Freedman and Cassell, 1994a) and receive a strong unidirectional cussed earlier, neurons in the PVT appear to become more active

input from cerebral cortex or cortical-like structures like the baso- when experimental animals are exposed to conditions involving

lateral amygdala and subiculum (Cassell et al., 1999; McDonald food rewards, administration of addictive drugs, or stressors of var-

et al., 1999). Fourth, the subcortical areas that are innervated by ious types. A common feature of these diverse activating conditions

the PVT are the same as the subcortical areas innervated by the is that they are associated with states of high arousal. In addition

cortical targets of the PVT. For example, the PVT projects to the to these diffuse projection systems, the PVT receives input from

infralimbic, prelimbic, and dysgranular/agranular insular cortical the infralimbic, prelimbic, and insular cortices. The signals trans-

areas whereas ﬁbers from these cortical areas and the PVT project mitted from prefrontal cortical areas may help guide behavior in

densely to the NAc, BST, and CeA (Groenewegen and Berendse, response to emotionally salient information. Indeed, reports show-

1994; Groenewegen et al., 1997). More speciﬁcally, PVT and infral- ing that neurons in the PVT are activated in rats after being exposed

imbic/prelimbic afferents terminate within NAc (Berendse et al., to cues or contexts previously associated with positive and negative

324 G.J. Kirouac / Neuroscience and Biobehavioral Reviews 56 (2015) 315–329

Fig. 5. The diagram represents a generalized view of the major inputs and outputs of the paraventricular nucleus of the thalamus (PVT). Anatomical evidence indicates that

the PVT is innervated by heterogeneously distributed neurons in the brainstem and hypothalamus, many of which appear to have visceral and arousal related functions.

In turn, the PVT provides a dense projection to a continuum that includes the nucleus accumbens and the central division of the extended amygdala. The PVT is also

reciprocally connected to the prefrontal cortical areas that innervate the same areas of the nucleus accumbens and extended amygdala that receive the PVT afferents. These

anatomical connections place the PVT at a key nodal point to modulate the approach-avoidance and defensive behavioral responses possibly by integrating emotionally

relevant information from the brainstem, hypothalamus and prefrontal cortex.

emotional outcomes are consistent with the view that information in regulating behavioral responses with either positive or negative

about emotional saliency or some aspects of cognitive processes valences. In this case, changes in the activity in a subpopulation

associated with emotionally charged events is transmitted from of neurons would be related to signals related to these valences.

cortical areas to the PVT. In this way, convergence in the PVT of Another possibility is that the PVT functions as an emotional arousal

signals related to arousal from the brainstem and hypothalamus system in which changes in ﬁring rate (tonic activity) and ﬁring pat-

with signals related to the emotional saliency of contexts and cues tern (phasic or burst of activity) of neurons in the PVT contribute

from cortical-like structures may help promote the appropriate preferentially to both positive and negative behavioral responses.

behavioral responses to environmental challenges. For example, an increase in neuronal activity in the PVT may help

Studies using cFos as an indication of neuronal excitation have promote motivation related to goal directed behavior whereas

shown that the PVT is strongly activated by an aroused state excessive activation may lead to negative emotional responses. This

regardless of the emotional valence (positive or negative). While would be similar to how the locus coeruleus is postulated to func-

cFos has been useful for identifying conditions that activate the tion and consistent with the classical Yerkes-Dobson relationship

PVT, the expression of this gene does not provide information between arousal and performance (Aston-Jones and Cohen, 2005).

about temporal characteristics of this activation. Electrophysiologi- For example, some level of arousal is required for goal directed

cal recordings of PVT neurons during the acquisition and expression behavior to occur while extremely high levels of arousal may lead

of emotional behavior will be necessary to answers to a number of to inappropriate attention to irrelevant stimuli or those involving

questions regarding the type of information relayed by the PVT. For risk. However, it is also possible that the PVT relays speciﬁc types

example, do neurons in the PVT increase their ﬁring rate to the pre- of information in addition to more generalized arousal states. As

sentation of cues that predict an emotional or motivational state or discussed earlier information about context and cues related to

is it the behavioral response triggered by the cues that activate PVT? emotional saliency may inﬂuence PVT neurons and the circuits they

Does the activity of individual neurons change over the acquisition control. It is also possible that modality speciﬁc sensory informa-

and extinction of the learned behavioral responses? Do neurons tion may engage unique projection neurons in the PVT. A more

in the PVT respond to salient stimuli regardless of the emotional reﬁned research approach will be required to decipher exactly the

valence or do some neurons respond selectively to negative and type of information that inﬂuences the activity of neurons in the

positive valence stimuli? Answers to these questions would go a PVT.

long way in providing a better understanding of how the PVT ﬁts

within the complex circuitry that regulates behavior. Acknowledgements

Finally, an accumulating amount of evidence implicates the PVT

in both positive and negative emotional responses. What is the pos- This work was supported by a grant MOP89758 to G.J.K. from

sible explanation for what appears to be functions with opposite the Canadian Institutes of Health Research. I would like to express

affective valences? One possibility is that subpopulations of neu- my gratitude to Sa Li for preparing the ﬁgures for the manuscript

rons within the PVT have selective projections that are involved as well as her efforts at improving the manuscript.

G.J. Kirouac / Neuroscience and Biobehavioral Reviews 56 (2015) 315–329 325

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