The neurophysiological basis of stress and anxiety - comparing neuronal diversity in the bed nucleus of the stria terminalis (BNST) across species

Abstract

The bed nucleus of the stria terminalis (BNST), as part of the extended amygdala, has become a region of increasing interest regarding its role in numerous human stress-related psychiatric diseases, including post-traumatic stress disorder and generalized anxiety disorder amongst others. The BNST is a sexually dimorphic and highly complex structure as already evident by its anatomy consisting of 11 to 18 distinct sub-nuclei in rodents. Located in the ventral forebrain, the BNST is anatomically and functionally connected to many other limbic structures, including the amygdala, hypothalamic nuclei, basal ganglia, and hippocampus. Given this extensive connectivity, the BNST is thought to play a central and critical role in the integration of information on hedonic-valence, mood, arousal states, processing emotional information, and in general shape motivated and stress/anxiety-related behavior. Regarding its role in regulating stress and anxiety behavior the anterolateral group of the BNST (BNST_ALG) has been extensively studied and contains a wide variety of neurons that differ in their electrophysiological properties, morphology, spatial organization, neuropeptidergic content and input and output synaptic organization which shape their activity and function. In addition to this great diversity, further species-specific differences are evident on multiple levels. For example, classic studies performed in adult rat brain identified three distinct neuron types (Type I-III) based on their electrophysiological properties and ion channel expression. Whilst similar neurons have been identified in other animal species, such as mice and non-human primates such as macaques, cross-species comparisons have revealed intriguing differences such as their comparative prevalence in the BNST_ALG as well as their electrophysiological and morphological properties, amongst other differences. Given this tremendous complexity on multiple levels, the comprehensive elucidation of the BNST_ALG circuitry and its role in regulating stress/anxiety-related behavior is a major challenge. In the present Review we bring together and highlight the key differences in BNST_ALG structure, functional connectivity, the electrophysiological and morphological properties, and neuropeptidergic profiles of BNST_ALG neurons between species with the aim to facilitate future studies of this important nucleus in relation to human disease.

Keywords: bed nucleus of the stria terminalis (BNST); cross-species; electrophysiology; human; macaque; neurpeptides; rodents.

FIGURE 1

BNST anatomy and nomenclature in different species. (A) Main nuclei of the BNST in the rat [Paxinos (1995) The Rat Brain in Stereotaxic Coordinates, 2nd edition]. (B) Main nuclei of the BNST in the mouse. (C) The BNST in the macaque (Paxinos et al., 2000). The Macaque Brain in Stereotaxic Coordinates, 2nd edn.). (D) Main nuclei of the BNST in the human [Mai (2016). Atlas of the Human Brain. 4th Ed.]. Subnuclei are colored based on their anatomic similarities. AC = anterior commissure, al = anterolateral BNST, am = anteromedial BSNT, c = central BNST, IC = internal capsule, ju = juxtacapsular BNST, l = lateral BNST, ld = laterodorsal BNST, lp = lateral posterior BNST, li = lateral intermediate BNST, m = medial BNST, ma = medial anterior BNST, mpi = medial posterointermediate BNST, mpl = medial posterolateral BNST, mpm = medial posteromedial BNST, mv = medioventral BNST, ov = oval BNST, p = posterior BNST, v = ventral BNST.

FIGURE 2

Electrophysiological characteristics of BNST neurons in three different species (rat, mouse and macaque). Each BNST neuron type displays a unique firing pattern due to the presence of certain combinations of ionic currents. (A) Type I neurons display similar firing characteristics across species: a regular firing pattern with depolarizing current steps and a prominent sag with hyperpolarizing current steps. (B) Type II neurons in both rats and macaques, but not mice, exhibit burst firing. Note the prominent rebound spike/burst after hyperpolarization in rats which is not evident in macaques. In mice on the other hand, certain Type II neurons display rebound firing while others do not (e.g., in specific trace shown here). (C) Type III neurons in all three species display a delay in action potential firing with depolarizing current steps and a prominent inward rectification with hyperpolarization current steps. Traces adapted from Daniel et al. (2017) with kind permission. I_h = hyperpolarization-activated non-specific cation current, I_T = low-threshold calcium (Ca²⁺) current, I_A = transient voltage-dependent potassium (K⁺) current, I_K(IR) = inward rectifying potassium (K⁺) current.

FIGURE 3

Neurochemical content of neurons in different BNST_ALG subnuclei of the rat, mouse, macaque and human. AC = anterior commissure, al = anterolateral BNST, am = anteromedial BNST, c = central BNST, IC = internal capsule, l = lateral BNST, ld = laterodorsal BNST, lj = lateral juxtacapsular BNST, lp = lateral posterior BNST, m = medial BNST, ma = medial anterior BNST ov = oval BNST, CRF = corticotropin releasing factor, DYN = dynorphin, ENK = enkephalin, NPY = neuropeptide Y, NT = neurotensin, PKC-delta = protein kinase C type delta, SOM = somatostatin.